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]

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Variant: NM_001270448.2:c.415T>C

CA397723375

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4f8bae2e-fb18-4cb8-9752-4ba96c4f9bb4

Approved on: 2023-11-13

Published on: 2023-11-13

HGVS expressions

NM_001270448.2:c.415T>C

NC_000017.11:g.7221972T>C

CM000679.2:g.7221972T>C

NC_000017.10:g.7125291T>C

CM000679.1:g.7125291T>C

NC_000017.9:g.7066015T>C

NG_007975.1:g.7139T>C

NG_008391.2:g.3079A>G

ENST00000356839.10:c.643T>C

ENST00000322910.9:c.*598T>C

ENST00000350303.9:c.577T>C

ENST00000356839.9:c.643T>C

ENST00000543245.6:c.712T>C

ENST00000577191.5:n.720T>C

ENST00000577857.5:n.459T>C

ENST00000579286.5:n.824T>C

ENST00000580365.1:n.374T>C

ENST00000581378.5:c.361T>C

ENST00000581562.5:n.545T>C

ENST00000582379.1:n.27T>C

ENST00000583312.5:c.658T>C

ENST00000583760.1:n.425T>C

NM_000018.3:c.643T>C

NM_001033859.2:c.577T>C

NM_001270447.1:c.712T>C

NM_001270448.1:c.415T>C

NM_000018.4:c.643T>C

NM_001033859.3:c.577T>C

NM_001270447.2:c.712T>C

Likely Pathogenic

PP3 PP4_Moderate PM1 PM3_Supporting PM2_Supporting

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(ACADVL): c.643T>C variant in ACADVL is a missense variant predicted to cause substitution of cystine by arginine at amino acid 215 (p.Cys215Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant is detected in at least one patient in homozygous fashion (PM3 point 0.5, PM3_Supporting, PMID: 25834949). This patient displayed reduced enzyme levels (< 5% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 25834949). This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). The computational predictor REVEL gives a score of 0.951, 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: PM1, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).

PP3

The computational predictor REVEL gives a score of 0.951, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).

PP4_Moderate

This patient displayed reduced enzyme levels (< 5% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 25834949).

PM1

This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1).

PM3_Supporting

The variant is detected in at least one patient in homozygous fashion (PM3 point 0.5, PM3_Supporting, PMID: 25834949).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

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