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.1220G>C (p.Gly407Ala)

CA287439291

474878 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 46830bcc-6b37-4ddd-8c85-9c43a0a4c089

HGVS expressions

NM_000018.4:c.1220G>C

NM_000018.4(ACADVL):c.1220G>C (p.Gly407Ala)

NC_000017.11:g.7223681G>C

CM000679.2:g.7223681G>C

NC_000017.10:g.7127000G>C

CM000679.1:g.7127000G>C

NC_000017.9:g.7067724G>C

NG_007975.1:g.8848G>C

NG_008391.2:g.1370C>G

NG_033038.1:g.15864C>G

ENST00000356839.10:c.1220G>C

ENST00000322910.9:c.*1175G>C

ENST00000350303.9:c.1154G>C

ENST00000356839.9:c.1220G>C

ENST00000542255.6:n.78G>C

ENST00000543245.6:c.1289G>C

ENST00000578579.2:n.391G>C

ENST00000578711.1:n.177G>C

ENST00000578824.5:n.636G>C

ENST00000579425.5:n.244G>C

ENST00000579546.1:n.57G>C

ENST00000583858.5:n.249G>C

ENST00000585203.6:n.428G>C

NM_000018.3:c.1220G>C

NM_001033859.2:c.1154G>C

NM_001270447.1:c.1289G>C

NM_001270448.1:c.992G>C

NM_001033859.3:c.1154G>C

NM_001270447.2:c.1289G>C

NM_001270448.2:c.992G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP1 PP3 PP4_Moderate 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.1220G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 407 (p.Gly407Ala) and is also known as Gly367Ala in the fully processed protein. This variant has been reported as occurring in trans to a known pathogenic variant in a pair of siblings with positive newborn screens and reduced very long chain acyl-CoA dehydrogenase (VLCAD) activity (PMID: 28755359, PM3, PP1, PP4_moderate). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305, 23798014). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.803, 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 VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP1, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021).

PP1

The variant has been reported to segregate with very long chain acyl CoA dehydrogenase (VLCAD) deficiency in 2 affected siblings from 1 family (PP1; PMID: 28755359).

PP3

The computational predictor REVEL gives a score of 0.803, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).

PP4_Moderate

This variant has been reported as occurring in trans to a known pathogenic variant in a pair of siblings with positive newborn screens and reduced VLCAD activity (PMID: 28755359, PM3, PP4_moderate).

PM3

This variant has been reported as occurring in trans to a known pathogenic variant in a pair of siblings with positive newborn screens and reduced VLCAD activity (PMID: 28755359, PM3, PP4_moderate).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

Approved on: 2023-02-13

Published on: 2023-02-13

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