Variant: NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter)

CA274997

194317 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 18582346-288f-4289-903c-5939c2d10243

HGVS expressions

NM_000018.4:c.1357C>T
NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter)
NC_000017.11:g.7223992C>T
CM000679.2:g.7223992C>T
NC_000017.10:g.7127311C>T
CM000679.1:g.7127311C>T
NC_000017.9:g.7068035C>T
NG_007975.1:g.9159C>T
NG_008391.2:g.1059G>A
NG_033038.1:g.15553G>A
ENST00000356839.10:c.1357C>T
ENST00000322910.9:c.*1312C>T
ENST00000350303.9:c.1291C>T
ENST00000356839.9:c.1357C>T
ENST00000542255.6:n.215C>T
ENST00000543245.6:c.1426C>T
ENST00000578711.1:n.488C>T
ENST00000579425.5:n.473C>T
ENST00000579546.1:n.194C>T
ENST00000579894.5:n.68C>T
ENST00000583074.5:n.76C>T
ENST00000583850.5:n.132C>T
ENST00000583858.5:n.386C>T
ENST00000585203.6:n.548C>T
NM_000018.3:c.1357C>T
NM_001033859.2:c.1291C>T
NM_001270447.1:c.1426C>T
NM_001270448.1:c.1129C>T
NM_001033859.3:c.1291C>T
NM_001270447.2:c.1426C>T
NM_001270448.2:c.1129C>T

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PM3

• Not Met criteria codes: PP4

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant was detected and confirmed in-trans with the pathogenic c.1349G>A (p.R450H) in a patient with VLCAD-deficiency (PM3, PMID:33150772). This variant was also reported in one patient with a positive newborn screen for VLCAD-deficiency (PMID:26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM3,PM2_Supporting.

Met criteria codes

• PM2_Supporting: 1 allele in gnomAD (MAF=0.000003978)
• PVS1: stop codon exon 14/20
• PM3: Family 4 ,table S1: Confirmed in trans with pathogenic p.R450H (9 family-study for VLCAD-deficiency. ) Points=1

Not Met criteria codes

• PP4: 1 allele from a large study for VLCADD/positive NBS

Approved on: 2022-12-15

Published on: 2022-12-15