Variant: NM_000018.4(ACADVL):c.1358G>A (p.Arg453Gln)

CA8338089

374123 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 68d25f00-a585-4a77-a106-bbd2745af2fc

Approved on: 2023-09-26

Published on: 2023-09-26

HGVS expressions

NM_000018.4:c.1358G>A
NM_000018.4(ACADVL):c.1358G>A (p.Arg453Gln)
NC_000017.11:g.7223993G>A
CM000679.2:g.7223993G>A
NC_000017.10:g.7127312G>A
CM000679.1:g.7127312G>A
NC_000017.9:g.7068036G>A
NG_007975.1:g.9160G>A
NG_008391.2:g.1058C>T
NG_033038.1:g.15552C>T
ENST00000356839.10:c.1358G>A
ENST00000322910.9:c.*1313G>A
ENST00000350303.9:c.1292G>A
ENST00000356839.9:c.1358G>A
ENST00000542255.6:c.216G>A
ENST00000543245.6:c.1427G>A
ENST00000578711.1:n.489G>A
ENST00000579425.5:n.474G>A
ENST00000579546.1:c.195G>A
ENST00000579894.5:n.69G>A
ENST00000583074.5:n.77G>A
ENST00000583850.5:n.133G>A
ENST00000583858.5:c.387G>A
ENST00000585203.6:n.549G>A
NM_000018.3:c.1358G>A
NM_001033859.2:c.1292G>A
NM_001270447.1:c.1427G>A
NM_001270448.1:c.1130G>A
NM_001033859.3:c.1292G>A
NM_001270447.2:c.1427G>A
NM_001270448.2:c.1130G>A

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PP3 PM3

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1358G>A variant in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 453 (p.Arg453Gln). This variant has been identified in several individuals with a phenotype highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, at least three patients displayed beta oxidation flux of <20% of normal and at least two patients had abnormal newborn screen followed by plasma acylcarnitine analysis consistent with VLCAD deficiency (PP4_Moderate, PMIDs 20060901, 30194637, 33986768). Of those individuals, at least one was presumed compound heterozygous for this variant and a pathogenic ACADVL variant (PMID: 33986768, PM3 0.5 points). At least two individuals were homozygous for the variant (PMID: 30194637, 33986768, PM3 1 point) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008 in the African 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 0.974, 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 the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).

Met criteria codes

• PP4_Moderate: This variant has been identified in several individuals with a phenotype highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, at least three patients displayed beta oxidation flux of <20% of normal and at least two patients had abnormal newborn screen followed by plasma acylcarnitine analysis consistent with VLCAD deficiency (PP4_Moderate, PMIDs 20060901, 30194637, 33986768).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.974, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).
• PM3: Of those individuals, at least one was presumed compound heterozygous for this variant and a pathogenic (PMID: 33986768, PM3 0.5 points). At least two individuals were homozygous for the variant (PMID: 30194637, 33986768, PM3 1 point) (PM3).