Variant: NM_000018.4(ACADVL):c.1406G>A (p.Arg469Gln)

CA220197

92276 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 6e8b7ddb-d3d0-4774-8cd9-f8c0a79307dd

HGVS expressions

NM_000018.4:c.1406G>A
NM_000018.4(ACADVL):c.1406G>A (p.Arg469Gln)
NC_000017.11:g.7224041G>A
CM000679.2:g.7224041G>A
NC_000017.10:g.7127360G>A
CM000679.1:g.7127360G>A
NC_000017.9:g.7068084G>A
NG_007975.1:g.9208G>A
NG_008391.2:g.1010C>T
NG_033038.1:g.15504C>T
ENST00000356839.10:c.1406G>A
ENST00000322910.9:c.*1361G>A
ENST00000350303.9:c.1340G>A
ENST00000356839.9:c.1406G>A
ENST00000542255.6:n.264G>A
ENST00000543245.6:c.1475G>A
ENST00000578711.1:n.537G>A
ENST00000579425.5:n.522G>A
ENST00000579546.1:n.243G>A
ENST00000579894.5:n.117G>A
ENST00000583074.5:n.125G>A
ENST00000583850.5:n.181G>A
ENST00000583858.5:n.435G>A
ENST00000585203.6:n.597G>A
NM_000018.3:c.1406G>A
NM_001033859.2:c.1340G>A
NM_001270447.1:c.1475G>A
NM_001270448.1:c.1178G>A
NM_001033859.3:c.1340G>A
NM_001270447.2:c.1475G>A
NM_001270448.2:c.1178G>A

Likely Pathogenic

• Met criteria codes: PP3 PM1 PM3 PP4_Moderate PM5_Supporting PM2_Supporting

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specification: ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

ACADVL VCEP

The c.1406G>A variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 469 (p.Arg469Trp). This variant has been detected in 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency; of the 3 homozygous individuals, 2 were monozygotic twins; in one heterozygous individual, a second distinct pathogenic variant in ACADVL was not observed. (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). At least one patient with this variant displayed ACADVL enzyme activity of <20% of normal which is highly specific for VLCADD (PP4_Moderate, PMID: 25834949). Another missense variant c.1405C>T (p.Arg469Trp) [VCV000021017.19, PMIDs: 9973285, 17374501, 17999356] in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285) (PM1). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, 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: PM3, PP4_Moderate, PM5, PM1, PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-16-2022).

Met criteria codes

• PP3: PP3 is met. The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).
• PM1: PM1 is met. This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285) (PM1).
• PM3: PM3 is met. This variant has been detected in 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of the 3 homozygous individuals, 2 were monozygotic twins. In one heterozygous individual, a second distinct pathogenic variant in ACADVL was not observed. (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3).
• PP4_Moderate: PP4_Moderate is met. At least one patient with this variant displayed ACADVL enzyme activity of <20% of normal which is highly specific for VLCADD (PP4_Moderate, PMID: 25834949).
• PM5_Supporting: PM5_Supporting is met. Another missense variant c.1405C>T (p.Arg469Trp) [VCV000021017.19, PMIDs: 9973285, 17374501, 17999356] in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting).
• PM2_Supporting: PM2_Supporting is met. This variant is absent from gnomAD 2.1.1 (PM2_Supporting).

Approved on: 2022-10-12

Published on: 2022-10-12