Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • No CSPEC related information was provided by the message!
  • No Criteria Specification was provided in the publication event for the variant classifaction.
  • The Criteria Specification shown below is a best-estimate based on the VCEP, gene, disease, and publication date.

Variant: NM_000018.4:c.265C>T

CA397722455

Gene: ACADVL (HGNC:37)
Condition: very long chain acyl-CoA dehydrogenase deficiency (MONDO:0008723)
Inheritance Mode: Autosomal recessive inheritance
UUID: 0dd0d739-a540-4cbb-af0b-514f1c7a3f3c
Approved on: 2022-08-09
Published on: 2022-08-09

HGVS expressions

NM_000018.4:c.265C>T
NC_000017.11:g.7220664C>T
CM000679.2:g.7220664C>T
NC_000017.10:g.7123983C>T
CM000679.1:g.7123983C>T
NC_000017.9:g.7064707C>T
NG_007975.1:g.5831C>T
NG_008391.2:g.4387G>A
ENST00000356839.10:c.265C>T
ENST00000322910.9:c.*220C>T
ENST00000350303.9:c.199C>T
ENST00000356839.9:c.265C>T
ENST00000543245.6:c.334C>T
ENST00000577191.5:n.342C>T
ENST00000577433.5:n.473C>T
ENST00000577857.5:n.229-102C>T
ENST00000578269.5:n.712C>T
ENST00000578421.1:n.473C>T
ENST00000579286.5:n.446C>T
ENST00000579886.2:c.201+138C>T
ENST00000580263.5:n.429C>T
ENST00000581562.5:n.312C>T
ENST00000582056.5:n.355C>T
ENST00000582166.1:n.153C>T
ENST00000582356.5:n.464C>T
ENST00000583312.5:c.265C>T
ENST00000584103.5:c.265C>T
NM_000018.3:c.265C>T
NM_001033859.2:c.199C>T
NM_001270447.1:c.334C>T
NM_001270448.1:c.37C>T
NM_001033859.3:c.199C>T
NM_001270447.2:c.334C>T
NM_001270448.2:c.37C>T
More

Likely Pathogenic

Met criteria codes 5
PP4_Moderate PM2_Supporting PS3_Supporting PP3 PM3
Not Met criteria codes 1
PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
ACADVL VCEP
The c.265C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by serine at amino acid 89 (p.Pro89Ser). This variant has been reported in two individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or variably increased C14:1 acylcarnitine levels (PP4_moderate; PMIDs: 11914034, Russian Paper). In these same probands, the variant was detected once confirmed in-trans with a pathogenic variant (PM3; PMIDs: 11914034). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Site-directed mutagenesis expression showed impaired VLCAD enzyme activity (PS3_supporting; PMIDs: 11914034). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).
Met criteria codes
PP4_Moderate
One proband's fibroblasts show an ~83% VLCAD activity reduction ranging over multiple publications; another proband shows elevated C14:1 levels after taking l-carnitine.
PM2_Supporting
Not in gnomAD or ExAC
PS3_Supporting
The Pro89Ser variant displays variable enzyme activity depending on temperature, ranging from 7% to 32% of wild-type. Given that an insufficent number of variant controls were used, the maximum evidence available is PS3_supporting.
PP3
REVEL score of 0.922
PM3
This variant has been seen confirmed in-trans with c.1606-3_1606-2del variant (confirmed Pathogenic, 1 point) and not confirmed with a missense VUS (0 points). 1.0 points, would meet PM3 if c.1606-3_1606-2del were approved pathogenic.
Not Met criteria codes
PM1
PMID:17999356 and other publications assert little functional change in VLCAD structure when expressing the variant.
Curation History
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