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.865G>A (p.Gly289Arg)

CA8337873

370981 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 766653ae-7261-479b-91b4-683897d15917

HGVS expressions

NM_000018.4:c.865G>A

NM_000018.4(ACADVL):c.865G>A (p.Gly289Arg)

NC_000017.11:g.7222289G>A

CM000679.2:g.7222289G>A

NC_000017.10:g.7125608G>A

CM000679.1:g.7125608G>A

NC_000017.9:g.7066332G>A

NG_007975.1:g.7456G>A

NG_008391.2:g.2762C>T

ENST00000356839.10:c.865G>A

ENST00000322910.9:c.*820G>A

ENST00000350303.9:c.799G>A

ENST00000356839.9:c.865G>A

ENST00000543245.6:c.934G>A

ENST00000577191.5:n.1037G>A

ENST00000581378.5:n.583G>A

ENST00000582379.1:n.249G>A

NM_000018.3:c.865G>A

NM_001033859.2:c.799G>A

NM_001270447.1:c.934G>A

NM_001270448.1:c.637G>A

NM_001033859.3:c.799G>A

NM_001270447.2:c.934G>A

NM_001270448.2:c.637G>A

Likely Pathogenic

PP4_Moderate PS3_Supporting 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 c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID: 14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID: 14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate).

PP4_Moderate

5 patient reports of VLCADD, including C14:1 range 1-3uM.

PS3_Supporting

15% VLCAD activity from E.coli expressed. Unstable protein product.

PP3

REVEL = 0.824 (> 0.75)

PM3

2 patients with p.V243A 1 patient with p.I183Mfs* unknown phase points=1.5

PM2_Supporting

minor allele frequency (MAF) <0.001

Approved on: 2023-06-27

Published on: 2023-06-27

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