Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000018.4:c.1077+2T>A

CA397724300

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d250c95e-c88d-4ac1-9506-1284b154c09b

HGVS expressions

NM_000018.4:c.1077+2T>A

NC_000017.11:g.7222867T>A

CM000679.2:g.7222867T>A

NC_000017.10:g.7126186T>A

CM000679.1:g.7126186T>A

NC_000017.9:g.7066910T>A

NG_007975.1:g.8034T>A

NG_008391.2:g.2184A>T

ENST00000356839.10:c.1077+2T>A

ENST00000322910.9:c.*1032+2T>A

ENST00000350303.9:c.1011+2T>A

ENST00000356839.9:c.1077+2T>A

ENST00000543245.6:c.1146+2T>A

ENST00000578824.5:n.228T>A

ENST00000582379.1:n.463T>A

ENST00000583858.5:n.106+2T>A

ENST00000585203.6:n.20T>A

NM_000018.3:c.1077+2T>A

NM_001033859.2:c.1011+2T>A

NM_001270447.1:c.1146+2T>A

NM_001270448.1:c.849+2T>A

NM_001033859.3:c.1011+2T>A

NM_001270447.2:c.1146+2T>A

NM_001270448.2:c.849+2T>A

Pathogenic

PM2_Supporting PVS1 PP4_Moderate

PP3

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1077+2T>A (NM_000018.4) variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant been reported in one individual with very long chain acyl-CoA dehydrogenase deficiency in the literature with decreased VLCAD enzyme activity (PP4_moderate; PMID: 30194637). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1, PM2_supporting, PP4_Moderate.

PM2_Supporting

Not in gnomAD

PVS1

This splice-site variant is predicted to break the wild-type donor site, leading to Exon 10 skipping and a resulting frameshift that creates a termination codon in Exon 11 well before the penultimate exon. Therefore, this is predicted to undergo NMD and meets PVS1.

PP4_Moderate

One proband displays 8% VLCAD residual activity, less than the required 20% for PP4_moderate

PP3

Not used for canonical splice-site variants meeting PVS1

Approved on: 2022-09-22

Published on: 2022-09-22

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