ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.602A>G (p.Tyr201Cys)

dbSNP: rs1597525536
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV001200733 SCV004176821 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-11-28 reviewed by expert panel curation The c.602A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 201 (p.Tyr201Cys). This variant has been detected in a set of siblings that displayed increased C14:1 on newborn screen and reduced very long chain acyl CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate, PP1; PMID: 17457695, 14517516). These siblings were compound heterozygous for this variant and a likely pathogenic variant confirmed in trans by parental testing (PM3 0.5 points, PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, 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: PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001200733 SCV001364894 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.602A>G (NP_000009.1:p.Tyr201Cys) [GRCH38: NC_000017.11:g.7221662A>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Invitae RCV001200733 SCV004297747 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-11-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the ACADVL protein (p.Tyr201Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 14517516). ClinVar contains an entry for this variant (Variation ID: 932789). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr201 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.