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.433C>T (p.Gln145Ter)

CA274436

189159 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 42941ff1-d592-4553-a819-61df9f304302

Approved on: 2022-03-08

Published on: 2022-03-08

HGVS expressions

NM_000018.4:c.433C>T

NM_000018.4(ACADVL):c.433C>T (p.Gln145Ter)

NC_000017.11:g.7221014C>T

CM000679.2:g.7221014C>T

NC_000017.10:g.7124333C>T

CM000679.1:g.7124333C>T

NC_000017.9:g.7065057C>T

NG_007975.1:g.6181C>T

NG_008391.2:g.4037G>A

ENST00000356839.10:c.433C>T

ENST00000322910.9:c.*388C>T

ENST00000350303.9:c.367C>T

ENST00000356839.9:c.433C>T

ENST00000543245.6:c.502C>T

ENST00000577191.5:n.510C>T

ENST00000577433.5:n.641C>T

ENST00000577857.5:n.293+184C>T

ENST00000579286.5:n.614C>T

ENST00000579886.2:c.271C>T

ENST00000580365.1:n.164C>T

ENST00000581378.5:n.132C>T

ENST00000581562.5:n.480C>T

ENST00000582056.5:n.616C>T

ENST00000582166.1:n.414C>T

ENST00000583312.5:c.433C>T

ENST00000584103.5:c.466C>T

NM_000018.3:c.433C>T

NM_001033859.2:c.367C>T

NM_001270447.1:c.502C>T

NM_001270448.1:c.205C>T

NM_001033859.3:c.367C>T

NM_001270447.2:c.502C>T

NM_001270448.2:c.205C>T

Likely Pathogenic

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

PVS1 PM2_Supporting

PS1 PP3 PP4 PM4 PM5 PM3 PM1 BP7 BP3 BP1 BP2

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.433C>T (p.Gln145Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.11 (PM2_Supporting). 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

PVS1 is met; Nonsense at exon 6 of predominant transcript; predicted to undergo NMD; removes >10% protein length.

PM2_Supporting

PM2_Supporting is met; Variant is not observed in gnomAD, ExAC,1K and ESP.

PS1

PS1 is not met; Variant is a nonsense.

PP3

PP3 is not met; Variant is a nonsense; see PVS1 criteria.

PP4

PP4 is not met; One symptomatic VLCADD case was reported; variant in het state without an identifiable second ACADVL allele; no biochemical data for patient but authors mention that all patients investigated had abnormal acylcarnitine profiiles (PMID: 10384387).

PM4

PM4 is not met; Variant is a nonsense.

PM5

PM5 is not met; Variant is a nonsense.

PM3

PM3 is not met; One case reported carrying the variant (referred as c.433C>T p.(Gln105Ter) in heterozygous state. Based on the provided transcript ID X86556 the glutamine residue is actually found at amino acid position 145 and not position 105 (PMID: 103843887); however, by traditional nomenclature this is position 105. A subsequent publication by the same authors identified c.1358G>A; p.Arg453Gln on the opposite allele (PMID: 10384387); however, this substitution has not been evaluated by the ACADVL VCEP.

PM1

PM1 is not met; Variant is a nonsense; criteria is reserved for missense.

BP7

BP7 is not met; Variant is a nonsense.

BP3

BP3 is not met; Variant is a nonsense.

BP1

BP1 is not met; Variant is a nonsense.

BP2

BP2 is not met; Variant has not been observed in cis with a pathogenic variant in ACADVL.

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