Variant: NM_000018.4(ACADVL):c.541dup (p.His181fs)

CA397723118

932736 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: c7fb4c7f-e8f1-4b85-8190-55c2f183f3eb

Approved on: 2022-03-08

Published on: 2022-04-28

HGVS expressions

NM_000018.4:c.541dup
NM_000018.4(ACADVL):c.541dup (p.His181fs)
NC_000017.11:g.7221601dup
CM000679.2:g.7221601dup
NC_000017.10:g.7124920dup
CM000679.1:g.7124920dup
NC_000017.9:g.7065644dup
NG_007975.1:g.6768dup
NG_008391.2:g.3452dup
ENST00000356839.10:c.541dup
ENST00000322910.9:c.*496dup
ENST00000350303.9:c.475dup
ENST00000356839.9:c.541dup
ENST00000543245.6:c.610dup
ENST00000577191.5:n.618dup
ENST00000577433.5:n.749dup
ENST00000577857.5:n.357dup
ENST00000579286.5:n.722dup
ENST00000579886.2:c.379dup
ENST00000580365.1:n.272dup
ENST00000581378.5:n.259dup
ENST00000581562.5:n.525-351dup
ENST00000582166.1:n.522dup
ENST00000583312.5:c.541dup
ENST00000583760.1:n.323dup
NM_000018.3:c.541dup
NM_001033859.2:c.475dup
NM_001270447.1:c.610dup
NM_001270448.1:c.313dup
NM_001033859.3:c.475dup
NM_001270447.2:c.610dup
NM_001270448.2:c.313dup

Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PVS1

• Not Met criteria codes: PM3

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.541dup (p.His181fs)variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 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 patient with this variant displayed enzyme activity levels measured in lymphocytes of 6% of control values, which is highly specific for VLCAD deficiency (PP4_moderate, PMID 32463482). 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, PP4_moderate, PM2_supporting. VCEP specifications version2; 10/15/21.

Met criteria codes

• PP4_Moderate: At least one patient with this variant displayed enzyme levels measured in lymphocytes of 6% of control values, which is highly specific for VLCAD deficiency (PP4_moderate, PMID 32463482).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PVS1: The c.541dup (p.His181fs)variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124).

Not Met criteria codes

• PM3: This variant is reported in unconfirmed trans with another variant (c.1072A>G (p.Lys358Glu)) but this second variant is currently a VUS according to VCEP classification criteria and therefore no points are applied to PM3 for this evaluation.