The ACADM NM_000016.6:c.985A>G (NP_000007.1:p.(Lys329Glu)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Homozygous c.985A>G newborns showed 0–8% residual MCAD activity, with concordant protein misfolding and reduced activity in independent assays. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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.ACADM encodes medium-chain acyl-CoA dehydrogenase, a mitochondrial enzyme that begins the breakdown of medium-chain fatty acids for energy. Changes in ACADM cause medium-chain acyl-CoA dehydrogenase deficiency, which can lead to fasting-related low blood sugar, liver dysfunction, encephalopathy, and potentially death in infancy; it has no established cancer role.
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, strong: homozygous c.985A>G newborns showed 0–8% residual MCAD activity, with concordant protein misfolding and reduced activity in independent assays.
Met: reported affected-case versus normal-control counts give a continuity-corrected OR of 1053.0 (95% CI 52.7-21039), exceeding the >5.0 threshold with the CI excluding 1.
Met at supporting strength: affected individuals were homozygous and both parents were heterozygous, establishing two variant copies in trans for recessive MCADD.
Met at supporting: REVEL 0.695 meets the generic PP3 supporting threshold of >= 0.644 for this missense variant.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 and PS4 at strong strength satisfy the generic ACMG/AMP two-strong pathogenic rule, with additional PM3 and PP3 supporting evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 9,398 / 1,614,074 alleles. Recorded AF 0.00582253. Recorded homozygote count 19.
This variant is present in gnomAD v2.1 (AF= 0.0033276; MAF= 0.33276%, 941/282786 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00619492; MAF= 0.61949%, 800/129138 alleles, homozygotes = 0); grpmax FAF= 0.00591457.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.695. Refer to the recorded PP3/BP4 rationale for interpretation.
49 Pathogenic · 3 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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 · 7 not met · 13 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Segregation and de novo criteria remain unassessed because the available evidence lacks a qualifying proband-trio record, multiple affected-relative segregation data, or affected-relative non-segregation data.
Functional evidence supports PS3 at strong strength because the exact variant shows concordant loss of MCAD activity and abnormal protein behavior across a routine diagnostic lymphocyte assay, recombinant biochemical assays, and a eukaryotic-cell system.
BS3 is not met because no study demonstrates normal protein function or normal splicing for the exact variant.
PS4 is met from a directly reported affected-versus-normal comparison: 31/34 variant alleles in MCAD-deficient cases versus 0/58 control alleles, yielding a continuity-corrected OR of 1053.0 (95% CI 52.7-21039).
PP4 and BP5 remain not assessed because patient-specific phenotype/family-history and alternate-molecular-basis data are not available.
PP5 and BP6 are not met because generic rules do not permit ordinary laboratory submissions, aggregate ClinVar labels, or non-expert assertions to trigger these criteria, and no qualifying expert-panel assertion is present.
No criteria match.
PS3 is met at strong strength. The exact ACADM c.985A>G (p.Lys329Glu; mature-protein K304E) variant has been evaluated in multiple orthogonal functional systems. In a routine confirmatory diagnostic laboratory assay using lymphocytes and healthy controls, 21 homozygous newborns had residual MCAD activity of 0–8%, while unaffected control samples had normal activity; the same study states that residual MCAD activity testing was a routine confirmation-diagnostic procedure. Recombinant-protein studies showed abnormal oligomerization/aggregation and reduced maximal activity to 46% of wild type, and COS-7-cell studies documented altered conformation, disturbed FAD binding, and variant-associated functional derangement. These concordant results directly support a damaging effect on MCAD function. The evidence is strong, although the papers do not establish a single formally validated, reproducible clinical diagnostic assay specifically calibrated for this variant beyond the routine diagnostic activity assay.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. ... Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
PS4 is met under the ACMG/AMP definition requiring an affected-case prevalence significantly increased over controls, with OR >5.0 and a 95% CI excluding 1. PMID:2393404 reports the exact c.985A>G variant in 31 of 34 mutant alleles from MCAD-deficient cases and absent from 29 unrelated normal individuals (0 of 58 control alleles). Using the reported allele counts and a Haldane-Anscombe 0.5 continuity correction for the zero control count, the computed allele-level OR is 1053.0 with 95% CI 52.7-21039, which excludes 1.0. The governing comparison is ">5.0": 1053.0 > 5.0? yes; therefore PS4 is met. PMID:23151387 additionally reports 8 of 18 false-positive-screen infants heterozygous for c.985A>G and clinically unaffected/normal after evaluation, but this cohort was not used as the primary formal control comparison.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: 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.
ACADM-related MCADD is recessive. The exact NM_000016.6:c.985A>G (p.Lys329Glu) variant was reported in affected individuals as homozygous, and in one family both parents were heterozygous, providing parent-based evidence that the two variant copies were in trans. The same variant was also reported in compound heterozygotes with another ACADM mutation. This directly satisfies the recessive PM3 phase requirement; no stronger PM3 level is assigned because the supplied governing rules provide no quantitative strength thresholds.
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
The variant is a missense substitution, so the governing rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. REVEL is 0.695, which meets the generic PP3 supporting threshold of >= 0.644. BayesDel is not used because no generic ACMG-strength calibration is established for it.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PM2 is not met. The variant is present in population controls at frequencies far above the supplied generic PM2 supporting threshold of <=0.0001: gnomAD v4.1 all-comers AF=0.00582253 (0.582253%) with grpmax FAF=0.0073482 and 19 homozygotes, while gnomAD v2.1 non-cancer exomes show AF=0.00318773 (0.318773%) with 1 homozygote. A historical study reported absence from 29 unrelated normal individuals, but the much larger current population datasets demonstrate that the variant is neither absent nor extremely rare.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
PP5 is not met because the qualifying condition is not satisfied: ClinVar shows no expert-panel submission for this exact variant, only ordinary laboratory and aggregate assertions, and the relevant published evidence is available for independent evaluation. The PMID:2393404 and PMID:11349232 reports therefore cannot trigger PP5 under the stated generic rule.
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. The required filtering population frequency is gnomAD v4.1 grpmax FAF=0.0073482 (0.73482%), which is below the generic stand-alone threshold of >=0.05 (5%). The highest point estimate, 0.00747951 in European (non-Finnish) individuals from 8,825/1,179,890 alleles, is not used because the governing guidance requires grpmax FAF rather than popmax AF. The gnomAD v2.1 non-cancer exome result is also below threshold at AF=0.00318773 and does not alter the conclusion. The established pathogenic association does not permit ending classification with BA1 when the required FAF is below 5%.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met under the supplied generic frequency calibration. The required filtering frequency is gnomAD v4.1 grpmax FAF=0.0073482 (0.73482%), below the generic default threshold of >=0.01 (1%); the gnomAD v2.1 non-cancer exome AF=0.00318773 is also below 1%. The European (non-Finnish) point estimate of 0.00747951 is not substituted for FAF. Because the observed filtering frequency is below the default threshold, a maximum-credible-frequency calculation is not needed to establish BS1, and no BS1 call is made from population frequency.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The available functional studies do not show no damaging effect on protein function or splicing; instead, they consistently report markedly reduced residual activity in homozygous c.985A>G newborns, reduced recombinant enzyme activity, abnormal oligomerization/aggregation, and structural or stability abnormalities. No well-established benign functional assay result for this exact variant was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, so the governing rule selects the REVEL path only; SpliceAI cannot provide BP4 support for this missense variant. REVEL is 0.695, which is above the generic BP4 supporting threshold of <= 0.29, so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established for it.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP6 is not met because no exact-variant ClinVar expert-panel classification of benign or likely benign is present. ClinVar instead contains pathogenic/likely pathogenic laboratory and aggregate submissions, with zero expert-panel submissions; these ordinary submissions cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is NP_000007.1:p.(Lys329Glu), and the reviewed literature establishes the exact NM_000016.6:c.985A>G change as pathogenic. However, the reviewed sources do not identify a previously established pathogenic ACADM variant caused by a different nucleotide change that produces the same Lys329Glu amino-acid substitution. The exact same nucleotide change cannot satisfy the alternate-nucleotide requirement for PS1, and no reliable alternate-codon comparator was available.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
The available evidence does not establish a specific affected proband with no family history carrying NM_000016.6:c.985A>G as a de novo variant with both maternity and paternity confirmed. PMID:2393404 instead reports affected individuals with the variant in the context of homozygosity and states that both parents in one family were heterozygous, which is inheritance evidence rather than de novo evidence. ClinVar origin labels such as de novo are submission metadata without documented trio testing, parental identities, maternity confirmation, paternity confirmation, or phenotype details in the reviewed evidence.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
ACADM has no retrieved VCEP specification or authoritative domain table. The case evidence reports that p.Lys329Glu is in the C-terminal alpha-domain, but that description alone does not establish a mutational hotspot or a critical, well-established functional domain without benign variation under generic PM1. Cancer Hotspots reports that this variant does not lie in a statistically significant hotspot, and COSMIC reports no somatic occurrence. The required domain criticality and absence-of-benign-variation evidence are therefore insufficient.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The target residue is Lys329 and the observed change is p.Lys329Glu. The reviewed evidence establishes the exact c.985A>G variant, but no different missense substitution at residue 329 with a reliable pathogenic determination was identified in the supplied evidence. The available PM5 candidate artifact contains zero same-residue candidates and explicitly does not support automatic application, so PM5 cannot be assessed from it.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available evidence does not document a specific affected patient with NM_000016.6:c.985A>G assumed to be de novo. PMID:2393404 describes affected individuals with the variant and parental testing in one family, where both parents were heterozygous, but it does not describe an assumed de novo occurrence. ClinVar origin labels are insufficient to establish an assumed de novo event without case-level clinical and parental context.
Assumed de novo, but without confirmation of paternity and maternity.
The available evidence does not provide multiple affected family members carrying NM_000016.6:c.985A>G with documented phenotype concordance and segregation across informative meioses. PMID:2393404 reports multiple affected cases, but they are not presented as multiple affected members of one family; the one family with parental testing had both parents heterozygous and does not establish affected-relative co-segregation. No segregation count or family pedigree is available to support a stronger PP1 level.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The evidence supports that missense variation is an important disease mechanism in ACADM: p.Lys329Glu is a common disease-associated missense variant and multiple studies describe pathogenic ACADM missense alleles. However, the supplied evidence does not establish the gene-level requirement of a low rate of benign missense variation. A pathogenic variant's frequency or a set of pathogenic missense reports cannot substitute for that missing benign-missense-rate assessment.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence describes MCAD-deficient cohorts and unaffected newborn-screen carriers but does not provide this case's phenotype or family history, so PP4 cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD v4.1 reports 19 homozygotes, including 18 in European (non-Finnish) individuals; gnomAD v2.1 reports 1 homozygote, the non-cancer exome subset reports 1, and gnomAD v3.1 non-cancer genomes report 0. These aggregate population records do not establish that any homozygote was a healthy adult, nor provide individual-level age, phenotype, or clinical follow-up. Homozygote observation alone therefore cannot satisfy the ACMG/AMP BS2 definition.
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.
No affected family members are documented who lack NM_000016.6:c.985A>G despite informative testing. PMID:2393404 describes parental heterozygosity in one family but does not establish that either parent was affected, nor does it provide an affected-relative non-segregation analysis. Therefore, lack of segregation cannot be evaluated, and the phenocopy and multiple-pathogenic-variant caveats cannot be assessed.
Lack of segregation in affected members of a family.
The supplied evidence does not establish that ACADM-related disease is caused primarily by truncating variants. Instead, the reviewed material documents multiple disease-associated missense variants, including the exact p.Lys329Glu variant, but that observation alone is not a systematic comparison of truncating and missense disease mechanisms and cannot determine whether BP1 applies.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
No evidence in the supplied case establishes this variant in cis with another pathogenic variant, and the available observations concern the recessive biallelic context rather than the BP2 dominant-gene trans configuration. Therefore the BP2 observation requirement cannot be assessed from the available phase data.
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 BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The available records do not identify an alternate molecular diagnosis in a case carrying NM_000016.6:c.985A>G, so BP5 cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
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_000016.6:c.985A>G in ACADM is a missense substitution predicted to produce NP_000007.1:p.(Lys329Glu). 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 ACADM, 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_000016.6:c.985A>G in ACADM is a missense substitution predicted to produce NP_000007.1:p.(Lys329Glu). 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 ACADM, 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_000016.6:c.985A>G in ACADM is a missense substitution predicted to produce NP_000007.1:p.(Lys329Glu). 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 ACADM, 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_000016.6:c.985A>G in ACADM is a missense substitution predicted to produce NP_000007.1:p.(Lys329Glu). 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 ACADM, 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 ACADM, mapped onto the exon structure of NM_000016.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)8825 / 1,179,890 | 0.007518 hom |
| Remaining individuals259 / 62,508 | 0.0041 |
| Admixed American87 / 60,030 | 0.0014 |
| European (Finnish)87 / 64,032 | 0.00141 hom |
| African/African American91 / 75,072 | 0.0012 |
| Ashkenazi Jewish25 / 29,604 | 0.00084 |
| South Asian24 / 91,090 | 0.00026 |
| European (non-Finnish)800 / 129,138 | 0.0062 |
| Remaining individuals24 / 7,220 | 0.00331 hom |
| African/African American33 / 24,948 | 0.0013 |
| European (Finnish)27 / 25,124 | 0.0011 |
| Ashkenazi Jewish11 / 10,370 | 0.0011 |
| Admixed American37 / 35,440 | 0.001 |
| South Asian9 / 30,602 | 0.00029 |
This variant is present in gnomAD v4.1 (AF= 0.00582253; MAF= 0.58225%, 9398/1614074 alleles, homozygotes = 19) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00747951; MAF= 0.74795%, 8825/1179890 alleles, homozygotes = 18); grpmax FAF= 0.0073482.
This variant is present in gnomAD v2.1 (AF= 0.0033276; MAF= 0.33276%, 941/282786 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00619492; MAF= 0.61949%, 800/129138 alleles, homozygotes = 0); grpmax FAF= 0.00591457.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, so the governing rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. REVEL is 0.695, which meets the generic PP3 supporting threshold of >= 0.644. BayesDel is not used because no generic ACMG-strength calibration is established for it.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so the governing rule selects the REVEL path only; SpliceAI cannot provide BP4 support for this missense variant. REVEL is 0.695, which is above the generic BP4 supporting threshold of <= 0.29, so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established for it.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... 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_000016.6:c.985A>G in ACADM is a missense substitution predicted to produce NP_000007.1:p.(Lys329Glu). 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 ACADM, 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 predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.695. BayesDel score = 0.444234.
12 paper records listed. 5 cited in the classification.
Reduced maximal activities were found in variants A27V (38% of wild-type), D241G (48%) and K304E (46%).
Location Results sections on disturbed oligomerization, enzyme kinetic parameters, thermal inactivation, and thermal denaturation
Context Recombinant wild-type and variant MCAD proteins expressed in a prokaryotic system with an MBP tag; oligomerization assessed by size-exclusion chromatography with or without GroESL co-overexpression, and enzyme kinetics measured for octanoyl-CoA oxidation.
Twenty-one newborns were characterized as homozygous for the prevalent mutation c.985A>G (# 17–37). They all presented with very low residual activities ranging from 0 to 8%.
Location Results, Genotype and Effect on Enzyme Function; Table 1
Context Cohort of 65 newborns suspected of MCAD deficiency after abnormal newborn screening; residual MCAD activity was measured in lymphocytes by octanoyl-CoA oxidation using HPLC-ESI-MS/MS and HPLC-UV, with anonymous healthy volunteer controls.
Eight of 18 were found to be heterozygous for the common mutation (c.985A>G); all 8 carriers with the common mutation were born at >36 weeks gestation and birth weight was appropriate for gestational age (mean 3.22 kg).
Location Results and Discussion, section 3.3, “False positive NBS results”
Context ACADM sequencing of dried-blood-spot DNA from 18 infants with false-positive newborn screening for MCAD deficiency; screening used octanoylcarnitine (C8), with PCR/NcoI analysis and subsequent coding-region sequencing.
Sequencing of MCAD cDNAs derived from fibroblast cultures from patients with MCAD deficiency identified an A to G replacement at nucleotide 985 in all three cultures.
Location Results, pp. 500–503; Discussion, p. 503
Context MCAD cDNA sequencing from fibroblast cultures of three patients, analysis of 14 additional MCAD-deficiency cases, enzyme-activity measurements, 29 normal controls, and parental testing in one family.
Eighty percent of symptomatic patients diagnosed before the establishment of expanded NBS programs in Europe and in the US are homozygous for the mutation p.Lys329Glu (c.985A>G)
Location Introduction; Materials and Methods, Mutations; Results; Table 3
Context Purified recombinant MCAD, COS-7-cell expression and enzyme-activity assays, circular dichroism, differential scanning fluorimetry, aggregation measurements, and thermal-inactivation kinetics.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00582253; MAF= 0.58225%, 9398/1614074 alleles, homozygotes = 19) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00747951; MAF= 0.74795%, 8825/1179890 alleles, homozygotes = 18); grpmax FAF= 0.0073482.
This variant is present in gnomAD v2.1 (AF= 0.0033276; MAF= 0.33276%, 941/282786 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00619492; MAF= 0.61949%, 800/129138 alleles, homozygotes = 0); grpmax FAF= 0.00591457.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (49 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 3586)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.695. BayesDel score = 0.444234.
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.