Submissions for variant NM_005518.4(HMGCS2):c.803G>A (p.Arg268Gln)

gnomAD frequency: 0.00006  dbSNP: rs371306326

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001097609	SCV001253904	uncertain significance	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001097609	SCV001486092	uncertain significance	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2020-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 268 of the HMGCS2 protein (p.Arg268Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with HMGCS2-related conditions. This variant is present in population databases (rs371306326, ExAC 0.03%).
Ambry Genetics	RCV004629449	SCV005121975	uncertain significance	Inborn genetic diseases	2024-03-19	criteria provided, single submitter	clinical testing	The c.803G>A (p.R268Q) alteration is located in exon 4 (coding exon 4) of the HMGCS2 gene. This alteration results from a G to A substitution at nucleotide position 803, causing the arginine (R) at amino acid position 268 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.