Submissions for variant NM_005518.4(HMGCS2):c.1514G>A (p.Arg505Gln)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002606687	SCV003503216	uncertain significance	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2022-05-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 505 of the HMGCS2 protein (p.Arg505Gln). This variant is present in population databases (rs758519315, gnomAD 0.006%). This missense change has been observed in individuals with HMG-CoA synthase-2 deficiency (PMID: 25511235, 29597274). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 29597274). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700959	SCV005203534	uncertain significance	not specified	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: HMGCS2 c.1514G>A (p.Arg505Gln) results in a conservative amino acid change located in the Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain (IPR013746) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251292 control chromosomes. c.1514G>A has been reported in the literature in homozygous or compound heterozygous individuals affected with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Puisac_2018, Pitt_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 70% of normal HMG-CoA synthase activity when expressed in E. coli (Puisac_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29597274, 25511235). ClinVar contains an entry for this variant (Variation ID: 2186499). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.