Variant: NM_000018.4(ACADVL):c.1146G>C (p.Lys382Asn)

CA16607872

389672 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 135b5d0f-4953-4f8d-81f6-b09d86a07858

Approved on: 2024-09-24

Published on: 2024-09-24

HGVS expressions

NM_000018.4:c.1146G>C
NM_000018.4(ACADVL):c.1146G>C (p.Lys382Asn)
NC_000017.11:g.7223201G>C
CM000679.2:g.7223201G>C
NC_000017.10:g.7126520G>C
CM000679.1:g.7126520G>C
NC_000017.9:g.7067244G>C
NG_007975.1:g.8368G>C
NG_008391.2:g.1850C>G
ENST00000356839.10:c.1146G>C
ENST00000322910.9:c.*1101G>C
ENST00000350303.9:c.1080G>C
ENST00000356839.9:c.1146G>C
ENST00000542255.6:c.4G>C
ENST00000543245.6:c.1215G>C
ENST00000578579.2:n.95G>C
ENST00000578824.5:n.562G>C
ENST00000579425.5:n.170G>C
ENST00000582379.1:n.797G>C
ENST00000583858.5:c.175G>C
ENST00000585203.6:n.354G>C
NM_000018.3:c.1146G>C
NM_001033859.2:c.1080G>C
NM_001270447.1:c.1215G>C
NM_001270448.1:c.918G>C
NM_001033859.3:c.1080G>C
NM_001270447.2:c.1215G>C
NM_001270448.2:c.918G>C

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM3 PM1 PM2_Supporting PM5_Supporting

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1146G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 382 (p.Lys382Asn). Information provided to the ACADVL VCEP provided by an external clinical laboratory shows an elevated plasma C14:1 in an individual that that had c.848T>C (p.Val283Ala) confirmed in trans (PP4, PM3). Another missense variant c.1144A>C (p.Lys382Gln) (Variation ID: 1628) 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 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.91, 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 [CLASSIFICATION] 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: PM1, PM3, PM5_Supporting, PP3 PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021).

Met criteria codes

• PP4: Information provided to the ACADVL VCEP provided by an external clinical laboratory shows an elevated plasma C14:1 in an individual that that had c.848T>C (p.Val283Ala) confirmed in trans (PP4, PM3)
• PP3: The computational predictor REVEL gives a score of 0.91, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).
• PM3: Information provided to the ACADVL VCEP provided by an external clinical laboratory shows an elevated plasma C14:1 in an individual that that had c.848T>C (p.Val283Ala) confirmed in trans (PP4, PM3).
• 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).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PM5_Supporting: Another missense variant c.1144A>C (p.Lys382Gln) (Variation ID: 1628) 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).