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

dbSNP: rs1597525536

Total submissions: 3

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
Labcorp Genetics (formerly Invitae), Labcorp	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.