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.1144A>C (p.Lys382Gln)

CA251906

1628 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e2d06da7-66f4-420f-8b88-0e071052a712

HGVS expressions

NM_000018.4:c.1144A>C

NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln)

NC_000017.11:g.7223199A>C

CM000679.2:g.7223199A>C

NC_000017.10:g.7126518A>C

CM000679.1:g.7126518A>C

NC_000017.9:g.7067242A>C

NG_007975.1:g.8366A>C

NG_008391.2:g.1852T>G

ENST00000356839.10:c.1144A>C

ENST00000322910.9:c.*1099A>C

ENST00000350303.9:c.1078A>C

ENST00000356839.9:c.1144A>C

ENST00000542255.6:n.2A>C

ENST00000543245.6:c.1213A>C

ENST00000578579.2:n.93A>C

ENST00000578824.5:n.560A>C

ENST00000579425.5:n.168A>C

ENST00000582379.1:n.795A>C

ENST00000583858.5:n.173A>C

ENST00000585203.6:n.352A>C

NM_000018.3:c.1144A>C

NM_001033859.2:c.1078A>C

NM_001270447.1:c.1213A>C

NM_001270448.1:c.916A>C

NM_001033859.3:c.1078A>C

NM_001270447.2:c.1213A>C

NM_001270448.2:c.916A>C

Likely Pathogenic

PP3 PP4_Moderate PM1 PM3 PM2_Supporting PS3_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(ACADVL):c.1144A>C (p.Lys382Gln) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 382. The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), 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 an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who was compound heterozygous for the variant and a pathogenic variant confirmed in trans by molecular subcloning (PM3, PMID: 8554073). The reported patient with this variant displayed reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID: 7769092). VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PS3_Supporting, PMID: 8554073). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.95, 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 ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PM3, PP3, PM2_Supporting, PS3_Supporting, PP4_Moderate).

PP3

The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3)

PP4_Moderate

At least one patient with this variant displayed much reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID: 7769092)

PM1

This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901)

PM3

This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who were compound heterozygous for the variant and a pathogenic variant and confirmed in trans by molecular subcloning (PM3)

PM2_Supporting

The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), which is lower than the ClinGen ACADVL VCEP threshold (< 0.001) for PM2_supporting, meeting this criterion (PM2_surpporting)

PS3_Supporting

VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PMID: 8554073)(PS3_Supporting)

Approved on: 2022-12-15

Published on: 2022-12-15

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