The BTD NM_001370658.1:c.1270G>C (NP_001357587.1:p.(Asp424His)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: HEK293 intracellular activity was 46.4 ± 21.2% of wild type, but culture-medium activity was 115.8 ± 38.2% and assay variability limited strength. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.BTD encodes biotinidase, an enzyme that recycles biotin from biocytin and other products of carboxylase breakdown, helping maintain the body’s supply of free biotin. Changes in BTD cause biotinidase deficiency, an inherited disorder that can impair biotin-dependent metabolism. BTD is not known to have a primary role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting: HEK293 intracellular activity was 46.4 ± 21.2% of wild type, but culture-medium activity was 115.8 ± 38.2% and assay variability limited strength.
Met: pooled 30/64 case alleles vs gnomAD v4.1 non-Finnish European 4.19% gives OR 20.19 (95% CI 12.35-32.98), above the >5.0 PS4 threshold.
Met at supporting: missense REVEL 0.769 meets the >=0.644 PP3 threshold but not the >=0.773 moderate threshold.
Met: P1020 had c.1270G>C in cis with truncating Q95X, reported on the same allele and consistent with a pathogenic BTD variant.
Likely Pathogenic: PS4 (strong) plus PS3 and PP3 (supporting) satisfy the generic ACMG/AMP combination rule; BP2 does not satisfy a benign rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 61,497 / 1,614,178 alleles. Recorded AF 0.038098. Recorded homozygote count 1308.
This variant is present in gnomAD v2.1 (AF= 0.0318389; MAF= 3.18389%, 9005/282830 alleles, homozygotes = 199) and has highest observed frequency in the European (Finnish) population (AF= 0.0555777; MAF= 5.55777%, 1396/25118 alleles, homozygotes = 53); grpmax FAF= 0.0387354.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.769. Refer to the recorded PP3/BP4 rationale for interpretation.
44 Pathogenic · 7 Likely pathogenic · 2 pathogenic · 2 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 12 not met · 8 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
None of the five requested codon, residue, domain, or gene-mechanism criteria is met for BTD c.1270G>C (p.Asp424His).
The c.1330G>C/p.Asp444His nomenclature in the literature represents the same nucleotide and amino-acid change under alternate numbering and does not independently satisfy PS1 or PM5.
No segregation, non-segregation, or proband-specific de novo evidence sufficient to apply PS2, PM6, PP1, or BS4 was identified.
The reviewed BTD literature reports affected individuals carrying the D444H-equivalent variant, but does not provide the parental and family-level data required for these criteria.
PS4 is met at strong strength: two independent case series (PMID 9654207, 18/19 partial-deficiency patients carrying D444H; PMID 11313766, 12/13) give an OR of 20.19 (95% CI 12.35-32.98) against the matched-ancestry gnomAD v4.1 non-Finnish European frequency of 4.19%, computed here from allele counts because neither paper prints an odds ratio; the OR exceeds 5.0 and the CI excludes 1.0.
PP4 could not be assessed because the case is a variant-only submission with no proband phenotype, biochemical result or family history.
PP5 is not met: the ClinVar Pathogenic label is aggregate laboratory opinion with zero expert-panel submissions and conflicting classifications, and independent functional and case-control evidence was available.
BP5 is not met: every reported carrier has a BTD-based explanation for the deficiency, with no case attributed to an alternate molecular basis.
BP6 is not met: no benign or likely benign reputable-source assertion exists for the variant, and there is no expert-panel review.
Population evidence does not support PM2 or BA1: the variant is common, but the filtering grpmax FAF remains below the 5% BA1 threshold.
BS1 requires human review because the frequency is above the generic default while BTD partial-deficiency penetrance, prevalence, and allelic heterogeneity prevent safe use of that default without a maximum-credible-frequency calculation.
BS2 cannot be established from aggregate homozygote counts without individual-level confirmation of healthy adult status.
No criteria match.
PS3 is met at supporting strength. The exact amino-acid substitution is described under the alternate BTD numbering c.1330G>C (p.Asp444His), corresponding to NM_001370658.1:c.1270G>C, p.(Asp424His). In three independent HEK293 transfection experiments, intracellular biotinidase activity was 46.4 ± 21.2% of wild type, supporting reduced protein function. However, activity in culture medium was not reduced (115.8 ± 38.2% of wild type), the authors reported substantial variability and possible enzyme lability, and the study was not a validated, reproducible clinical diagnostic assay. These limitations support downgrading the functional evidence to supporting rather than applying uncalibrated strong PS3. The clinical serum-activity observations in PMID:15776412 are concordant with partial deficiency but are confounded by additional BTD variants and therefore are not treated as independent decisive functional evidence.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
c.1270G>C p.(Asp424H) is the BTD c.1330G>C p.Asp444His (D444H) substitution under the legacy numbering; the papers discussing D444H describe this same allele. Two independent case series report how often affected individuals carry it. Swango et al. 1998 (PMID 9654207): 18 of 19 randomly selected individuals with partial biotinidase deficiency carried D444H on one allele, and the authors estimated the population frequency at 0.039. Muehl et al. 2001 (PMID 11313766): 12 of 13 unrelated patients with partial biotinidase deficiency carried D444H in at least one allele. Neither paper prints an odds ratio, but each reports carrier counts in affected patients against a quantified population frequency, which is a case-control comparison; I treated each heterozygous patient as one variant allele and computed the OR myself. Cases: 30 variant alleles among 64 (30 of 32 affected individuals heterozygous). Controls: matched-ancestry gnomAD v4.1 European (non-Finnish), 49,419/1,180,024 = 0.04188 (the cohorts are Turkish, Polish, German and Austrian, so NFE is the appropriate control). OR = (30/34)/(49,419/1,130,605) = 20.19, 95% CI 12.35-32.98 by the Woolf method; each series alone gives 20.59 (10.89-38.93) and 19.61 (9.07-42.40), and the paper's own 0.039 population frequency gives 22.18. The Hungarian healthy-subject screen (PMID 20549359; D444H frequency 5.5% in 100 unaffected subjects) is consistent with the gnomAD control frequency. Operator check, read from this criterion's own governing note (an enrichment rule in which a higher OR is stronger, met when the OR is greater than 5.0 with a CI excluding 1.0): '20.19 > 5.0 ? yes' and '95% CI 12.35-32.98 excludes 1.0 ? yes'. PS4 is therefore met at its default strong strength. Caveats recorded for review: both series were ascertained on the partial-deficiency biochemical phenotype (10-30% activity), the pooled sample is small (32 individuals), and the allele is common in gnomAD v4.1 overall (3.81%, 1,308 homozygotes), so the enrichment demonstrated is specific to the partial/mild phenotype; the absolute-frequency consequences are population-criterion questions (BS1/BA1) rather than PS4 questions.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls....Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The variant is a missense substitution, NM_001370658.1:c.1270G>C (p.Asp424His), so the governing generic PP3 path is REVEL only; SpliceAI is not used for this missense assessment. REVEL is 0.769, which meets the supplied generic PP3 supporting threshold of >= 0.644 but does not meet the moderate threshold of >= 0.773. The PP3 supporting criterion is therefore met. The supplied REVEL threshold is the ClinGen SVI calibration of Pejaver et al. 2022 (PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PMID:15776412 reports the target D444H variant under the alternate c.1330G>C numbering in P1020 on both alleles, with 283C>T (Q95X) on the second target-bearing allele. Q95X is reported as a termination codon causing truncation near the beginning of the enzyme, establishing the target variant in cis with a pathogenic truncating BTD variant. This satisfies the cis branch of BP2 for an autosomal recessive disorder.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The target is BTD c.1270G>C, p.Asp424His, also reported as c.1330G>C, p.Asp444His under an alternate numbering convention. This is the same nucleotide and amino-acid change, not a previously established pathogenic variant with a different nucleotide change producing the same amino-acid substitution. The available literature therefore does not establish an independent same-amino-acid PS1 comparator.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
BTD p.Asp424His is not supported by the available evidence as lying in a recognized mutational hotspot or a critical, well-established functional domain without benign variation. The Cancer Hotspots result is negative, COSMIC reports no somatic occurrence for the queried variant, and no VCEP domain table or approved domain list is available for BTD. The available functional paper shows altered activity for the variant but does not establish that residue 424 is a PM1-qualifying domain or hotspot.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met because the variant is common in population databases. Using the default all-comers sources because no governing VCEP specifies a non-cancer or exome-only source, the variant has AF 0.0318389 with 199 homozygotes in gnomAD v2.1 and AF 0.0380980 with 1308 homozygotes in gnomAD v4.1. These frequencies are far above the generic PM2 supporting threshold of <=0.0001; the non-cancer subsets also show substantial frequency (v2.1 exomes AF 0.0319338, 167 homozygotes; v3.1 non-cancer AF 0.0292917, 92 homozygotes).
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
No different missense substitution at BTD residue Asp424 with an independently established pathogenic interpretation was identified. The available D444H/c.1330G>C literature is the same target variant under alternate numbering, while the collected comparator artifact contains no same-residue candidates.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP2 requires both a low rate of benign missense variation and missense variants as a common disease mechanism. The BTD target variant itself is present in gnomAD v4.1 at allele frequency 0.038098, with 1,308 homozygotes, demonstrating substantial population missense variation inconsistent with a low benign-missense rate. Although BTD disease literature includes missense disease alleles, the combined PP2 requirement is not satisfied.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
ClinVar holds an exact match for this variant (ClinVar variation ID 1900) as Pathogenic, but the review status is 'criteria provided, conflicting classifications' and the submission audit lists 0 expert-panel submissions: the four exact-variant submissions are three clinical laboratories (Mass General Brigham LMM, Johns Hopkins Genomics, Quest Diagnostics) plus one OMIM literature-only record with no assertion criteria, alongside 44 laboratory Pathogenic, 7 Likely pathogenic and 2 Uncertain significance submissions in the aggregate. Under the generic rule, PP5 is triggered only by an exact-variant expert-panel classification, so aggregate ClinVar labels and ordinary laboratory submissions must not be used here. PP5's own precondition also fails: the rule requires that the evidence not be available to the laboratory for independent evaluation, whereas independent functional evidence (PMID 31337602: p.Asp444His expression in HEK293 cells, 46.4 +/- 21.2% of wild-type activity in lysate) and independent population/case-control evidence (gnomAD and the case series assessed under PS4) were available and were used. PP5 is therefore not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. Under the generic default, BA1 requires grpmax FAF >=0.05. The relevant all-comers gnomAD values are grpmax FAF 0.0387354 in gnomAD v2.1 and 0.0415699 in gnomAD v4.1, both below 0.05. Although the Finnish population point estimates exceed 5% (0.0555777 in v2.1 and 0.05293 in v4.1), the governing instruction requires the filtering grpmax FAF rather than popmax point estimate; the Finnish sample has more than 2000 observed alleles, so the failure is the FAF threshold, not a small-population exclusion. The variant is also reported as pathogenic/likely pathogenic in ClinVar, which is concordant with not applying a stand-alone benign BA1 call.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS3 is not met. The available variant-specific functional study does not show no damaging effect on protein function: intracellular biotinidase activity was reduced to 46.4 ± 21.2% of wild type, despite normal activity in culture medium. The mixed compartment-specific results cannot be used as well-established evidence of preserved protein function, and the clinical observations in PMID:15776412 are not benign functional evidence because they involve additional BTD variants and partial-deficiency biochemical activity.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available BTD evidence does not establish that disease-causing variants are primarily truncating. The literature documents multiple missense disease alleles and identifies D444H, corresponding to the target under alternate numbering, as a recurrent BTD missense variant associated with partial deficiency. Therefore the BP1 gene-level premise is not supported.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is missense, so the governing generic BP4 path is REVEL only; SpliceAI cannot be substituted or combined. REVEL is 0.769, above the supplied BP4 supporting cutoff of <= 0.29 and within the indeterminate interval, so BP4 is not met. SpliceAI returned no score, which is missing data and cannot support BP4; BayesDel has no generic ACMG-strength calibration and is not used.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
No report places this variant in a patient whose disease was attributed to an alternate molecular basis. In PMID 15776412 the patients carrying D444H have their deficiency explained by their BTD genotypes - P1020 is D444H on one allele with Q95X (c.283C>T) overriding the second D444H, P1018 is D444H in trans with P391S plus G445V, P987 carries A171T+D444H with Q511E - so the second allele is a further BTD allele, which is allelic evidence for biotinidase deficiency, not an alternate molecular basis for the disease. The partial-deficiency series (PMID 9654207, 18/19 carriers; PMID 11313766, 12/13 carriers; PMID 21752405, p.D444H among the most common alleles in 21 patients) likewise attribute the biochemical phenotype to biallelic BTD variants rather than to another gene, and the ClinVar exact-variant submissions carry the condition 'biotinidase deficiency' or 'not provided', with no submitter reporting an alternative explanation. The criterion's own situation - an affected individual carrying the variant but explained by another cause - is not documented anywhere in the reviewed literature, so BP5 is not met.
Variant found in a case with an alternate molecular basis for disease.
No reputable source reports this variant as benign or likely benign. The exact-variant ClinVar record (variation ID 1900) contains only Pathogenic (44 laboratories), Likely pathogenic (7), Pathogenic (2) and Uncertain significance (2) submissions, with no Benign or Likely benign assertion, and the review status is 'criteria provided, conflicting classifications'. The submission audit shows 0 expert-panel submissions, so even if a benign assertion existed it could not be used under the generic rule, which requires an exact-variant expert-panel classification; aggregate ClinVar labels and ordinary laboratory submissions must not trigger BP6. Both of BP6's preconditions therefore fail: there is no reputable-source benign report, and independent evidence was available to the laboratory. BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available evidence does not document a de novo occurrence of NM_001370658.1:c.1270G>C (p.Asp424His) in a proband. The literature reports affected individuals with the D444H equivalent and states that parental blood was obtained when possible to confirm allelic assignment, but it does not provide confirmed maternity and paternity for a specific proband carrying this variant, nor establish absence of family history. Therefore PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
BTD deficiency is autosomal recessive. PMID:15776412 reports the target D444H variant in affected individuals with other BTD variants and describes phase in P1020 and P1018, but it does not establish a separately pathogenic variant in trans with the target: P1020 has D444H on both alleles, with Q95X reported in cis on one D444H-bearing allele, while P1018 has D444H on one allele and P391S/G445V on the other without an explicit pathogenic designation for the trans allele. The available evidence therefore does not satisfy the required pathogenic-in-trans condition.
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
The available evidence does not document an assumed de novo occurrence of NM_001370658.1:c.1270G>C (p.Asp424His) in a proband. Although the literature discusses parental samples in some affected children, it does not identify a specific proband with this variant and demonstrate that the variant was absent from the parents without confirming both parentage. Therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
The available evidence reports the D444H equivalent in several affected individuals, generally with other BTD variants, but does not document co-segregation of NM_001370658.1:c.1270G>C (p.Asp424His) with disease in multiple affected family members. The paper's parental-testing statement concerns allelic assignment when possible and is not segregation evidence across affected relatives. No meioses, pedigree, affected-relative genotypes, or segregation count are available, so PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The case record is a variant-only submission: there is no proband clinical description, no HPO terms, no serum biotinidase activity result and no family history, so the patient's phenotype specificity for a single-gene disease cannot be judged and PP4 cannot be evaluated. Nothing in the evidence bundle supplies phenotype information about the individual being tested; the papers reviewed describe biotinidase deficiency at cohort level. Two points would also need to be settled if a phenotype were supplied. First, the biotinidase deficiency phenotype itself (seizures, hypotonia, ataxia, skin rash, alopecia, hearing loss, optic atrophy) is shared with other inborn errors of biotin metabolism, notably holocarboxylase synthetase deficiency, and partial deficiency is frequently asymptomatic, so a documented, unusually specific presentation would be required rather than the diagnosis label alone. Second, PP4 applies to a patient's phenotype or family history, not to a variant's known disease association, so a gene-level match cannot substitute for clinical data.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS1 is not assessed rather than applied from the 1% default alone. The filtering grpmax FAF is 0.0387354 in gnomAD v2.1 and 0.0415699 in gnomAD v4.1, both above the generic 0.01 default, with the elevated frequency concentrated in Finnish individuals but based on more than 2000 observed alleles. However, BTD deficiency is autosomal recessive, this variant is associated with partial biotinidase deficiency and asymptomatic or variably affected individuals are described in the case evidence, so a high carrier frequency cannot be judged against the default without a maximum-credible-allele-frequency calculation incorporating disease prevalence, penetrance, and allelic heterogeneity. Those inputs and a validated per-gene calculation are not available here; therefore the elevated frequency does not by itself establish BS1.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS2 is not assessed. The variant is observed in many gnomAD homozygotes, including 199 in gnomAD v2.1 and 1308 in gnomAD v4.1, but the available aggregate population records do not identify individual ages, health status, biotinidase activity, newborn-screening history, treatment status, or whether each homozygote is a healthy adult. Because BS2 requires observation in a healthy adult for a recessive disorder, homozygote counts alone do not establish the criterion.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The available evidence does not identify affected family members who lack NM_001370658.1:c.1270G>C (p.Asp424His), and it provides no pedigree-based non-segregation analysis. Reports of the variant in affected individuals, including individuals with additional BTD variants, do not establish lack of segregation in an affected family. Therefore BS4 cannot be assessed.
Lack of segregation in affected members of a family.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001370658.1:c.1270G>C in BTD is a missense substitution predicted to produce NP_001357587.1:p.(Asp424His). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for BTD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001370658.1:c.1270G>C in BTD is a missense substitution predicted to produce NP_001357587.1:p.(Asp424His). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for BTD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001370658.1:c.1270G>C in BTD is a missense substitution predicted to produce NP_001357587.1:p.(Asp424His). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for BTD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001370658.1:c.1270G>C in BTD is a missense substitution predicted to produce NP_001357587.1:p.(Asp424His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for BTD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in BTD, mapped onto the exon structure of NM_001370658.1. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)3389 / 64,028 | 0.053106 hom |
| European (non-Finnish)49419 / 1,180,024 | 0.0421009 hom |
| Remaining individuals2399 / 62,510 | 0.03856 hom |
| South Asian3383 / 91,080 | 0.03799 hom |
| Ashkenazi Jewish963 / 29,604 | 0.03316 hom |
| Middle Eastern130 / 6,062 | 0.0211 hom |
| Admixed American1286 / 60,028 | 0.02117 hom |
| African/African American521 / 75,044 | 0.00694 hom |
| East Asian7 / 44,886 | 0.00016 |
| European (Finnish)1396 / 25,118 | 0.05653 hom |
| European (non-Finnish)5119 / 129,150 | 0.0496 hom |
| South Asian1129 / 30,616 | 0.03731 hom |
| Ashkenazi Jewish340 / 10,368 | 0.0335 hom |
| Remaining individuals217 / 7,222 | 0.035 hom |
| Admixed American643 / 35,436 | 0.0188 hom |
| African/African American159 / 24,966 | 0.00641 hom |
| East Asian2 / 19,954 | 0.0001 |
This variant is present in gnomAD v4.1 (AF= 0.038098; MAF= 3.80980%, 61497/1614178 alleles, homozygotes = 1308) and has highest observed frequency in the European (Finnish) population (AF= 0.05293; MAF= 5.29300%, 3389/64028 alleles, homozygotes = 106); grpmax FAF= 0.0415699.
This variant is present in gnomAD v2.1 (AF= 0.0318389; MAF= 3.18389%, 9005/282830 alleles, homozygotes = 199) and has highest observed frequency in the European (Finnish) population (AF= 0.0555777; MAF= 5.55777%, 1396/25118 alleles, homozygotes = 53); grpmax FAF= 0.0387354.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_001370658.1:c.1270G>C (p.Asp424His), so the governing generic PP3 path is REVEL only; SpliceAI is not used for this missense assessment. REVEL is 0.769, which meets the supplied generic PP3 supporting threshold of >= 0.644 but does not meet the moderate threshold of >= 0.773. The PP3 supporting criterion is therefore met. The supplied REVEL threshold is the ClinGen SVI calibration of Pejaver et al. 2022 (PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is missense, so the governing generic BP4 path is REVEL only; SpliceAI cannot be substituted or combined. REVEL is 0.769, above the supplied BP4 supporting cutoff of <= 0.29 and within the indeterminate interval, so BP4 is not met. SpliceAI returned no score, which is missing data and cannot support BP4; BayesDel has no generic ACMG-strength calibration and is not used.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001370658.1:c.1270G>C in BTD is a missense substitution predicted to produce NP_001357587.1:p.(Asp424His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for BTD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.769. BayesDel score = 0.269042.
10 paper records listed. 4 cited in the classification.
Because newborn screening should result in complete ascertainment of mutations causing profound biotinidase deficiency (less than 10% of mean normal serum activity), we compared the mutations in a group of 59 children with profound biotinidase deficiency who were identified by newborn screening in the United States with 33 children ascertained by exhibiting symptoms.
Location Abstract
Context 59 newborn-screening-ascertained and 33 symptomatically ascertained US children with profound biotinidase deficiency; BTD mutation analysis.
P1018 is a child with partial deficiency who has the characteristic 1330G>C mutation on one allele (Swango et al. 1998). On the other allele there are two alterations, the first, 1171C>T, results in a substitution of a serine for a proline, but has been observed previously and results in no decrease in enzyme activity (Hymes et al. 2001). Therefore, the loss of activity in this situation must be due to the second mutation 1334G>T that results in the substitution of a glycine by valine at position 445 of the enzyme.
Location Table 2; Results, paragraphs describing patients P1020 and P1018
Context Children with biotinidase deficiency identified by symptoms or newborn screening; serum biotinidase activity was measured by direct enzymatic assay, and BTD exonic and adjacent intronic regions were PCR-amplified and sequenced using reference sequence NM_000060.1.
More common mutations found among this group were p.D444H and the double mutation [p.D444H;p.A171T].
Location Abstract, Results
Context Two series of Spanish patients: 15 detected through newborn screening and 6 through selective screening for hearing loss or inherited metabolic disease; biochemical and BTD genetic analysis.
The p.Asp444His variant showed reduction on enzyme activity in cells (but not completely loss of activity) as seen in most of patients. However, in culture medium, we verified high activity.
Location Results, sections 3.1–3.3; Discussion, subsection ‘The polymorphic variant classically associated to partial BD: p.Asp444His’
Context BTD expression constructs transfected into HEK293 cells; biotinidase activity measured by colorimetric assay in cell lysates and culture medium across three independent transfection experiments, with western blot detection of the expressed protein; population frequency assessed using gnomAD, ABraOM, and a Southern Brazilian cohort.
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This variant is present in gnomAD v4.1 (AF= 0.038098; MAF= 3.80980%, 61497/1614178 alleles, homozygotes = 1308) and has highest observed frequency in the European (Finnish) population (AF= 0.05293; MAF= 5.29300%, 3389/64028 alleles, homozygotes = 106); grpmax FAF= 0.0415699.
This variant is present in gnomAD v2.1 (AF= 0.0318389; MAF= 3.18389%, 9005/282830 alleles, homozygotes = 199) and has highest observed frequency in the European (Finnish) population (AF= 0.0555777; MAF= 5.55777%, 1396/25118 alleles, homozygotes = 53); grpmax FAF= 0.0387354.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (44 clinical laboratories) and as Likely pathogenic (7 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 1900)
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.769. BayesDel score = 0.269042.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.