Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000018.4(ACADVL):c.637G>A (p.Ala213Thr)

CA275413

198683 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: abafbb81-6e27-41f7-b0c6-eab2acd05e4b

Approved on: 2024-04-15

Published on: 2024-04-15

HGVS expressions

NM_000018.4:c.637G>A

NM_000018.4(ACADVL):c.637G>A (p.Ala213Thr)

NC_000017.11:g.7221966G>A

CM000679.2:g.7221966G>A

NC_000017.10:g.7125285G>A

CM000679.1:g.7125285G>A

NC_000017.9:g.7066009G>A

NG_007975.1:g.7133G>A

NG_008391.2:g.3085C>T

ENST00000356839.10:c.637G>A

ENST00000322910.9:c.*592G>A

ENST00000350303.9:c.571G>A

ENST00000356839.9:c.637G>A

ENST00000543245.6:c.706G>A

ENST00000577191.5:n.714G>A

ENST00000577857.5:n.453G>A

ENST00000579286.5:n.818G>A

ENST00000580365.1:n.368G>A

ENST00000581378.5:c.355G>A

ENST00000581562.5:n.539G>A

ENST00000582379.1:n.21G>A

ENST00000583312.5:c.652G>A

ENST00000583760.1:n.419G>A

NM_000018.3:c.637G>A

NM_001033859.2:c.571G>A

NM_001270447.1:c.706G>A

NM_001270448.1:c.409G>A

NM_001033859.3:c.571G>A

NM_001270447.2:c.706G>A

NM_001270448.2:c.409G>A

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2_Supporting

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4 c.637G>A (p.Ala213Thr) in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 213 (p.Ala213Thr). The highest population minor allele frequency in gnomAD V2.1.1 is 0.00006 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in homozygous fashion in three consanguinity siblings affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, at least one of whom displayed reduced enzyme levels (17% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 1.0, PM3, PMID: 12213615). The computational predictor REVEL gives a score of 0.917, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021).

PP4_Moderate

This variant has been detected in homozygous fashion in three consanguinity siblings affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, at least one of whom displayed reduced enzyme levels (17% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 1.0, PM3, PMID: 12213615).

PP3

The computational predictor REVEL gives a score of 0.917, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).

PM3

PM2_Supporting

The highest population minor allele frequency in gnomAD V2.1.1 is 0.00006 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

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