Variant: NM_000018.4(ACADVL):c.253dup (p.Asp85fs)

CA624860683

943198 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: da874646-0e53-4091-b797-f7891aa7361c

HGVS expressions

NM_000018.4:c.253dup
NM_000018.4(ACADVL):c.253dup (p.Asp85fs)
NC_000017.11:g.7220652dup
CM000679.2:g.7220652dup
NC_000017.10:g.7123971dup
CM000679.1:g.7123971dup
NC_000017.9:g.7064695dup
NG_007975.1:g.5819dup
NG_008391.2:g.4399dup
ENST00000356839.10:c.253dup
ENST00000322910.9:c.*208dup
ENST00000350303.9:c.187dup
ENST00000356839.9:c.253dup
ENST00000543245.6:c.322dup
ENST00000577191.5:n.330dup
ENST00000577433.5:n.461dup
ENST00000577857.5:n.229-114dup
ENST00000578269.5:n.700dup
ENST00000578421.1:n.461dup
ENST00000579286.5:n.434dup
ENST00000579886.2:c.201+126dup
ENST00000580263.5:n.417dup
ENST00000581562.5:n.300dup
ENST00000582056.5:n.343dup
ENST00000582166.1:n.141dup
ENST00000582356.5:n.452dup
ENST00000583312.5:c.253dup
ENST00000584103.5:c.253dup
NM_000018.3:c.253dup
NM_001033859.2:c.187dup
NM_001270447.1:c.322dup
NM_001270448.1:c.25dup
NM_001033859.3:c.187dup
NM_001270447.2:c.322dup
NM_001270448.2:c.25dup

Pathogenic

• Met criteria codes: PVS1 PM3_Supporting PP4_Moderate PM2_Supporting

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4:c.253dup (p.Asp85Glyfs*19) variant in ACADVL is a one nucleotide duplication that results in a frameshift predicted to cause a premature stop codon in biologically-relevant-exon 5/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a distinct pathogenic (VCV000021025.27; c.848T>C, p.(Val283Ala); not confirmed in trans by parental testing. (PM3 points = 0.5, PMID: 27209629) (PM3_Supporting). At least one patient with this variant displayed >1.0uM C14::1 levels on initial NBS and asserted abnormal levels of plasma acylcarnitine levels at follow-up, which is highly specific for VLCADD (PMID: 27209629) (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001758 in NFE population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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: PVS1, PM3_Supporting, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 08/11/21).

Met criteria codes

• PVS1: PVS1 met. The c.253dup (p.Asp85Glyfs*19) variant in ACADVL is a one base duplication that results in a frameshift predicted to cause a premature stop codon in biologically-relevant-exon 5/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124).
• PM3_Supporting: PM3_supporting met. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (VCV000021025.27; c.848T>C, p.(Val283Ala); not confirmed in trans by parental testing. (PM3 points = 0.5, PMID: 27209629) (PM3_Supporting).
• PP4_Moderate: PP4_Moderate met. At least one patient with this variant displayed >1.0uM C14::1 levels on initial NBS and asserted abnormal levels of plasma acylcarnitine levels at follow-up, which is highly specific for VLCADD (PMID: 27209629). (PP4_Moderate)
• PM2_Supporting: PM2_supporting met. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001758 in NFE 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: 2022-04-06

Published on: 2022-04-06