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.308A>G (p.Lys103Arg)

CA8337646

254700 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 884bc1d2-6f20-4fa7-8b1e-722a8b7ef79f

Approved on: 2024-04-23

Published on: 2024-04-23

HGVS expressions

NM_000018.4:c.308A>G

NM_000018.4(ACADVL):c.308A>G (p.Lys103Arg)

NC_000017.11:g.7220796A>G

CM000679.2:g.7220796A>G

NC_000017.10:g.7124115A>G

CM000679.1:g.7124115A>G

NC_000017.9:g.7064839A>G

NG_007975.1:g.5963A>G

NG_008391.2:g.4255T>C

ENST00000356839.10:c.308A>G

ENST00000322910.9:c.*263A>G

ENST00000350303.9:c.242A>G

ENST00000356839.9:c.308A>G

ENST00000543245.6:c.377A>G

ENST00000577191.5:n.385A>G

ENST00000577433.5:n.516A>G

ENST00000577857.5:n.259A>G

ENST00000579286.5:n.489A>G

ENST00000579886.2:c.202-149A>G

ENST00000580365.1:n.39A>G

ENST00000581378.5:c.7A>G

ENST00000581562.5:n.355A>G

ENST00000582056.5:n.398A>G

ENST00000582166.1:n.196A>G

ENST00000582356.5:n.507A>G

ENST00000583312.5:c.308A>G

ENST00000584103.5:c.308A>G

NM_000018.3:c.308A>G

NM_001033859.2:c.242A>G

NM_001270447.1:c.377A>G

NM_001270448.1:c.80A>G

NM_001033859.3:c.242A>G

NM_001270447.2:c.377A>G

NM_001270448.2:c.80A>G

Uncertain Significance

BA1 BP4 PP4_Moderate

PM3 BP2

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.308A>G variant in ACADVL is a missense variant predicted to cause substitution of lysine by arginine at amino acid 103 (p.Lys103Arg). This variant has been reported in one individual with elevated C14:1 levels, an acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and a positive fatty acid oxidation probe assay, which are highly specific for VLCAD deficiency (PP4; PMID: 27209629). The highest population minor allele frequency in gnomAD v2.1.1 is 1.2% in the African population, which is higher than the ClinGen ACADVL threshold (0.7%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.35, which is below the threshold of 0.5 indicating that the variant does not predict a damaging effect on ACADVL function (BP4). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for VLCAD deficiency, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on April 23, 2024.

BA1

gnomAD frequency of 0.01178 with 4 total homozygotes between ExAC and gnomAD

BP4

REVEL Score of 0.353

PP4_Moderate

Proband shows significantly elevated C14:1 levels and other phenotypes characteristic of disease, but no enzyme activity level or follow-up plasma analysis.

PM3

Phase of variants not confirmed

BP2

Phase of variants not confirmed

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