Variant: NM_000018.4(ACADVL):c.1193_1194insGCA (p.Tyr398Ter)

CA1139665148

932851 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 883b111b-4053-404c-8658-5f95316498fa

HGVS expressions

NM_000018.4:c.1193_1194insGCA
NM_000018.4(ACADVL):c.1193_1194insGCA (p.Tyr398Ter)
NC_000017.11:g.7223654_7223655insGCA
CM000679.2:g.7223654_7223655insGCA
NC_000017.10:g.7126973_7126974insGCA
CM000679.1:g.7126973_7126974insGCA
NC_000017.9:g.7067697_7067698insGCA
NG_007975.1:g.8821_8822insGCA
NG_008391.2:g.1397_1398insGCT
NG_033038.1:g.15891_15892insGCT
ENST00000356839.10:c.1193_1194insGCA
ENST00000322910.9:c.*1148_*1149insGCA
ENST00000350303.9:c.1127_1128insGCA
ENST00000356839.9:c.1193_1194insGCA
ENST00000542255.6:n.51_52insGCA
ENST00000543245.6:c.1262_1263insGCA
ENST00000578579.2:n.364_365insGCA
ENST00000578711.1:n.150_151insGCA
ENST00000578824.5:n.609_610insGCA
ENST00000579425.5:n.217_218insGCA
ENST00000579546.1:n.30_31insGCA
ENST00000583858.5:n.222_223insGCA
ENST00000585203.6:n.401_402insGCA
NM_000018.3:c.1193_1194insGCA
NM_001033859.2:c.1127_1128insGCA
NM_001270447.1:c.1262_1263insGCA
NM_001270448.1:c.965_966insGCA
NM_001033859.3:c.1127_1128insGCA
NM_001270447.2:c.1262_1263insGCA
NM_001270448.2:c.965_966insGCA

Pathogenic

• Met criteria codes: PS1 PM2_Supporting PVS1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1193_1194insGCA; (p.Tyr398delinsTer) variant in ACADVL is a insertion variant predicted to cause an immediate premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The same amino acid change (p.Tyr398Ter), resulting from a different nucleotide change (c.1194C>A), is classified as pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PS1; PMID: 10529389, ClinVar ID: 810875). This variant is absent from gnomAD v2.1.1 (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, PS1, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021).

Met criteria codes

• PS1: An alternate pathogenic variant c.1194C>A results in the same protein change as this variant - namely p.Tyr398Ter. The c.1194C>A variant is reported in the literature in a proband with elevated C14:1 levels and VLCAD residual enzyme activity of 3.72% of normal controls. (Proposed pathogenic)
• PM2_Supporting: This variant is not found in population databases.
• PVS1: c.1193_1194insGCA (p.Tyr398delinsTer) is an inframe insertion that creates a stop codon (stop-gain) in exon 12 of the ACADVL gene at Tyr398. This altered transcript would be predicted to undergo nonsense mediated decay.

Approved on: 2022-12-14

Published on: 2022-12-14