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.605T>C (p.Leu202Pro)

CA220216

92288 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e9794637-c64a-46f9-baa2-f22fa0b1a3e7

HGVS expressions

NM_000018.4:c.605T>C

NM_000018.4(ACADVL):c.605T>C (p.Leu202Pro)

NC_000017.11:g.7221665T>C

CM000679.2:g.7221665T>C

NC_000017.10:g.7124984T>C

CM000679.1:g.7124984T>C

NC_000017.9:g.7065708T>C

NG_007975.1:g.6832T>C

NG_008391.2:g.3386A>G

ENST00000356839.10:c.605T>C

ENST00000322910.9:c.*560T>C

ENST00000350303.9:c.539T>C

ENST00000356839.9:c.605T>C

ENST00000543245.6:c.674T>C

ENST00000577191.5:n.682T>C

ENST00000577857.5:n.421T>C

ENST00000579286.5:n.786T>C

ENST00000579886.2:c.443T>C

ENST00000580365.1:n.336T>C

ENST00000581378.5:c.323T>C

ENST00000581562.5:n.525-287T>C

ENST00000583312.5:c.605T>C

ENST00000583760.1:n.387T>C

NM_000018.3:c.605T>C

NM_001033859.2:c.539T>C

NM_001270447.1:c.674T>C

NM_001270448.1:c.377T>C

NM_001033859.3:c.539T>C

NM_001270447.2:c.674T>C

NM_001270448.2:c.377T>C

Likely Pathogenic

PM2_Supporting PP3 PP4_Moderate PM3

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4 c.605T>C (p.Leu202Pro) in ACADVL is a missense variant predicted to cause substitution of leucine by proline at amino acid 202 (p. Leu202Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000004 in the general population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in apparently heterozygous fashion in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who also displayed reduced enzyme levels (20% and 26% of wildtype, respectively), which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 23480858, 30194637). At least one individual with this variant was identified by very long chain acyl-CoA dehydrogenase (VLCAD) clinical phenotype, who also carried a pathogenic variant c.848T>C in trans, displaying reduced enzyme levels (4% of wildtype) (PM3 score = 1.0, PM3, PMID: 30194637). The computational predictor REVEL gives a score of 0.953, 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 very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.000004 in the general population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.953, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).

PP4_Moderate

This variant has been detected in apparently heterozygous fashion in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who also displayed reduced enzyme levels (20% and 26% of wildtype, respectively), which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 23480858, 30194637).

PM3

At least one individual with this variant was identified by very long chain acyl-CoA dehydrogenase (VLCAD) clinical phenotype, who also carried a pathogenic variant c.848T>C in trans, displaying reduced enzyme levels (4% of wildtype) (PM3 score = 1.0, PM3, PMID: 30194637).

Approved on: 2024-03-26

Published on: 2024-03-26

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