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(ACADVL):c.603C>G (p.Tyr201Ter)

CA8337766

554491 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 408b3f5d-ed3a-4afa-9c00-19510b89bda0

HGVS expressions

NM_000018.4:c.603C>G

NM_000018.4(ACADVL):c.603C>G (p.Tyr201Ter)

NC_000017.11:g.7221663C>G

CM000679.2:g.7221663C>G

NC_000017.10:g.7124982C>G

CM000679.1:g.7124982C>G

NC_000017.9:g.7065706C>G

NG_007975.1:g.6830C>G

NG_008391.2:g.3388G>C

ENST00000356839.10:c.603C>G

ENST00000322910.9:c.*558C>G

ENST00000350303.9:c.537C>G

ENST00000356839.9:c.603C>G

ENST00000543245.6:c.672C>G

ENST00000577191.5:n.680C>G

ENST00000577857.5:n.419C>G

ENST00000579286.5:n.784C>G

ENST00000579886.2:c.441C>G

ENST00000580365.1:n.334C>G

ENST00000581378.5:n.321C>G

ENST00000581562.5:n.525-289C>G

ENST00000583312.5:c.603C>G

ENST00000583760.1:n.385C>G

NM_000018.3:c.603C>G

NM_001033859.2:c.537C>G

NM_001270447.1:c.672C>G

NM_001270448.1:c.375C>G

NM_001033859.3:c.537C>G

NM_001270447.2:c.672C>G

NM_001270448.2:c.375C>G

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM2_Supporting

PM1

Evidence Links 1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.603C>G (p.Tyr201Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant has been observed in only one publication with no information provided about the proband (PMID: 25087612). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_Supporting (VCEP specifications v2.0, approved on 09/16/2021).

PVS1

Nonsense variant that is predicted to undergo NMD and is present in biologically-relevant transcripts meets PVS1

PM2_Supporting

Allele frequency of 0.00006160 in African population in gnomAD

PM1

This termination takes place directly in the middle of the domain which interacts with the cofactor FAD which is critical for proper function and protein conformation, however PM1 is traditionally not used for terminations.

Provides evidence for functional effects in this domain PubMed:20060901

Approved on: 2022-03-08

Published on: 2022-03-08

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