Variant: NM_000018.4(ACADVL):c.1322G>A (p.Gly441Asp)

CA220193

21016 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 7632a574-ebef-41ce-8cb8-6a5028bf2de6

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000018.4:c.1322G>A
NM_000018.4(ACADVL):c.1322G>A (p.Gly441Asp)
NC_000017.11:g.7223865G>A
CM000679.2:g.7223865G>A
NC_000017.10:g.7127184G>A
CM000679.1:g.7127184G>A
NC_000017.9:g.7067908G>A
NG_007975.1:g.9032G>A
NG_008391.2:g.1186C>T
NG_033038.1:g.15680C>T
ENST00000356839.10:c.1322G>A
ENST00000322910.9:c.*1277G>A
ENST00000350303.9:c.1256G>A
ENST00000356839.9:c.1322G>A
ENST00000542255.6:n.180G>A
ENST00000543245.6:c.1391G>A
ENST00000578711.1:n.361G>A
ENST00000579425.5:n.346G>A
ENST00000579546.1:n.159G>A
ENST00000583074.5:n.41G>A
ENST00000583850.5:n.97G>A
ENST00000583858.5:n.351G>A
ENST00000585203.6:n.523+7G>A
NM_000018.3:c.1322G>A
NM_001033859.2:c.1256G>A
NM_001270447.1:c.1391G>A
NM_001270448.1:c.1094G>A
NM_001033859.3:c.1256G>A
NM_001270447.2:c.1391G>A
NM_001270448.2:c.1094G>A

Pathogenic

• Met criteria codes: PM3_Strong PP4_Moderate PP3 PM2 PM1

• Not Met criteria codes: BP4

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1322G>A (p.Gly441Asp) variant in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 441. At least two individuals with this variant displayed VLCAD enzyme activity <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 25834949). The variant has been described in the homozygous state in at least 4 affected individuals, confirmed in trans to a pathogenic variant in at least one individual, and in at least one individual with a distinct pathogenic variant without determination of phase of the variants (PM3_Strong; PMIDs: 1648817, 17999356, 24305961, 30194637, 32061778). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion. This variant occurs adjacent to the FAD binding pocket and is located on a loop that contributes to dimer formation (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.982, 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 pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021)

Met criteria codes

• PM3_Strong: Variant has been described in the homozygous state in at least 4 individuals. Confirmed in trans to p.Arg366His (VCEP LP) Not confirmed in trans to c.753-2A>C (P by VCEP).
• PP4_Moderate: 2 individuals in PMID 25834949 carried this variant and had VLCAD enzyme activity <20% of normal.
• PP3: The computational predictor REVEL gives a score of 0.982, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).
• PM2: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion
• PM1: PMID 20060901 shows this is adjacent to the FAD binding pocket and is part of a Gly-Gly-x-Gly domain on the loop between monomers, contributing to dimer formation.

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline