Submissions for variant NM_000018.4(ACADVL):c.1540G>A (p.Gly514Arg)

gnomAD frequency: 0.00001  dbSNP: rs370282954

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001802356	SCV002047784	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-06-09	criteria provided, single submitter	clinical testing	The ACADVL c.1540G>A; p.Gly514Arg variant (rs370282954), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 514 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.717). However, given the lack of clinical and functional data, the significance of the p.Gly514Arg variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001802356	SCV002228120	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-02-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1330697). A different variant (c.1540G>C) giving rise to the same protein effect has been determined to be pathogenic (Invitae). This suggests that this variant is also likely to be causative of disease. This variant is present in population databases (rs370282954, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 514 of the ACADVL protein (p.Gly514Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230697	SCV003929338	uncertain significance	not specified	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1540G>A (p.Gly514Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250538 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1540G>A in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.