Variant classification summary

NM_001370658.1:c.1270G>C

BTD · NP_001357587.1:p.(Asp424His) · NM_001370658.1

GRCh37: chr3:15686693 G>C · GRCh38: chr3:15645186 G>C

Gene: BTD Transcript: NM_001370658.1

Final call

Likely Pathogenic

PS3 supporting PS4 strong PP3 supporting BP2 supporting

Variant details

Gene

BTD

Transcript

NM_001370658.1

Protein

NP_001357587.1:p.(Asp424His)

gnomAD AF

0.038098028841924494 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Supporting pathogenic: HEK293 intracellular biotinidase activity was 46.4 ± 21.2% of wild type, with discordant medium activity limiting strength.

2

Strong pathogenic: affected-case enrichment gave OR 20.19 (95% CI 12.35–32.98), above the >5 threshold with the interval excluding 1.

3

Supporting pathogenic: REVEL 0.769 exceeds the generic PP3 threshold of 0.644.

4

Supporting benign criterion: the variant was in cis with truncating Q95X, but BP2 alone does not satisfy a benign rule or create conflict.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria yields Likely Pathogenic; the applied supporting BP2 criterion does not meet a benign rule.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the reported c.1330G>C/p.Asp444His record is the same nucleotide change under alternate numbering, not an independent nucleotide substitution producing Asp424His.	PMID:15776412 PMID:31337602
PS2	Not assessed	Not assessed: no proband-specific confirmation of both maternity and paternity, de novo status, and absence of family history is documented.	PMID:15776412
PS3	Met	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.	PMID:31337602 PMID:15776412
PS4	Met	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.	gnomad_v4 PMID:15776412 PMID:31337602 PMID:21752405
PM1	Not met	Not met: no approved BTD domain or hotspot evidence places residue 424 in a critical region without benign variation, and Cancer Hotspots is negative.	hotspots cosmic PMID:31337602
PM2	Not met	Not met: gnomAD v4.1 AF is 0.0380980 with 1308 homozygotes, far above the PM2 <=0.0001 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: affected cases show phase, but no separately established pathogenic BTD variant is confirmed in trans with c.1270G>C.	PMID:15776412
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different pathogenic missense substitution at BTD residue Asp424 was identified; D444H is the same target variant under alternate numbering.	pm5_candidates PMID:15776412 PMID:31337602
PM6	Not assessed	Not assessed: no specific affected proband is shown to carry the variant as assumed de novo without parental testing confirmation.	PMID:15776412
PP1	Not assessed	Not assessed: affected individuals are reported, but no multiple affected family members with variant-positive co-segregation or meioses are documented.	PMID:15776412
PP2	Not met	Not met: gnomAD v4.1 shows allele frequency 0.038098 and 1,308 homozygotes for this missense variant, inconsistent with a low benign-missense rate.	gnomad_v4 PMID:15776412
PP3	Met	Met at supporting: missense REVEL 0.769 meets the >=0.644 PP3 threshold but not the >=0.773 moderate threshold.	revel
PP4	Not assessed	Not assessed: no proband phenotype, biochemical result or family history is recorded, so phenotype specificity for a single-gene disorder cannot be judged.
PP5	Not met	Not met: ClinVar's Pathogenic label has zero expert-panel submissions, and independent functional and case-control evidence was available, so PP5's precondition fails.	clinvar PMID:31337602
BA1	Not met	Not met: gnomAD grpmax FAF is 0.0415699, below the 0.05 BA1 threshold despite a Finnish popmax point estimate above 5%.	gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS1	Not assessed	Not assessed: grpmax FAF reaches 0.0415699, but BTD partial-deficiency penetrance and disease-prevalence inputs needed to validate BS1 are unavailable.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD reports 1308 homozygotes, but individual adult health and biotinidase phenotypes are not documented.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: intracellular activity was 46.4 ± 21.2% of wild type, so the evidence does not show no damaging effect despite 115.8 ± 38.2% activity in medium.	PMID:31337602 PMID:15776412
BS4	Not assessed	Not assessed: no affected family members without the variant, pedigree, or documented non-segregation analysis is available.	PMID:15776412
BP1	Not met	Not met: BTD literature documents recurrent missense disease alleles, including D444H corresponding to this target, rather than primarily truncating disease variants.	PMID:15776412 PMID:31337602
BP2	Met	Met: P1020 had c.1270G>C in cis with truncating Q95X, reported on the same allele and consistent with a pathogenic BTD variant.	PMID:15776412
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.769 exceeds the <=0.29 BP4 supporting threshold, and unavailable SpliceAI cannot substitute.	revel spliceai
BP5	Not met	Not met: every reported carrier of this variant has a BTD-based explanation (e.g. D444H in trans with Q95X or P391S+G445V), and no case with an alternate molecular basis exists.	PMID:15776412 PMID:21752405 clinvar
BP6	Not met	Not met: ClinVar holds no benign or likely benign assertion for this variant (only 53 pathogenic/likely pathogenic and 2 uncertain submissions) and zero expert-panel reviews.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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