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_001270448.2:c.844A>G

CA8337932

2058739 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 41cdeb1d-1429-44b3-9d53-a81d81828202

Approved on: 2023-06-13

Published on: 2023-06-13

HGVS expressions

NM_001270448.2:c.844A>G

NC_000017.11:g.7222860A>G

CM000679.2:g.7222860A>G

NC_000017.10:g.7126179A>G

CM000679.1:g.7126179A>G

NC_000017.9:g.7066903A>G

NG_007975.1:g.8027A>G

NG_008391.2:g.2191T>C

ENST00000356839.10:c.1072A>G

ENST00000322910.9:c.*1027A>G

ENST00000350303.9:c.1006A>G

ENST00000356839.9:c.1072A>G

ENST00000543245.6:c.1141A>G

ENST00000578824.5:n.221A>G

ENST00000582379.1:n.456A>G

ENST00000583858.5:n.101A>G

ENST00000585203.6:n.13A>G

NM_000018.3:c.1072A>G

NM_001033859.2:c.1006A>G

NM_001270447.1:c.1141A>G

NM_001270448.1:c.844A>G

NM_000018.4:c.1072A>G

NM_001033859.3:c.1006A>G

NM_001270447.2:c.1141A>G

NM_000018.4(ACADVL):c.1072A>G (p.Lys358Glu)

Uncertain Significance

PP4_Moderate PM3 PM2_Supporting

PP3 PS3

Evidence Links 1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1072A>G (p.Lys358Glu) variant in ACADVL is a missense in exon 10. This variant has been reported twice as compound heterozygote with pathogenic variants (p.V283A & p.His181Profs72) in patients with ACADVL deficiency (PMID: 25834949, 21932095, PM3). Both patients with this variant displayed reduced enzyme activity, which is highly specific for ACADVL deficiency (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.69, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limiting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP4_moderate, PM3.

PP4_Moderate

At least one patient with this variant displayed residual enzyme activity levels at 13% of controls, which is highly specific for VLCAD (PP4_moderate, PMID 21932095). A second patient with VLCADD: up to 25% residual enzyme activity (PMID: 25834949)

PM3

This variant has been detected in at least 1 individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. One individual is compound heterozygous for the variant and a pathogenic variant not confirmed in trans and therefore 0.5 PM3 points are provided PMID 21932095 (PM3_supporting). A second patient is also reported with frameshift (p.His181ProfsX72) (PMID: 25834949). Points = 0.5 Total points = 1.0

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP3

REVEL below 0.75 (0.69)

PS3

Patient derived fibroblasts; do not use PS3_supporting, rather PP4_moderate From Diekman paper, figure 1 (PMID: 25834949) C16, C14, C12 = 0.2, 0.5, 0.6 (uM) patient #10 LC-FAO-flux ~50% at 37C C2 = 0.05 (uM) C12:C16, C14:C16, C14:C12 = 5, 4.5, 1 VLCAD assay % of controls temperatures (C) (40,37,30) = 2,6,25 FAO flux % of controls temperatures (C) (40,37,30)= 30,50,60

VLCAD assay below 25% of controls PubMed:25834949

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