Submissions for variant NM_005518.4(HMGCS2):c.1513C>T (p.Arg505Trp)

gnomAD frequency: 0.00003  dbSNP: rs780044819

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000402158	SCV000347901	uncertain significance	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2018-01-12	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	RCV000402158	SCV000819440	uncertain significance	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2022-12-08	criteria provided, single submitter	clinical testing	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 292328). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. This variant is present in population databases (rs780044819, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 505 of the HMGCS2 protein (p.Arg505Trp).
Ambry Genetics	RCV002519378	SCV003725533	uncertain significance	Inborn genetic diseases	2022-01-07	criteria provided, single submitter	clinical testing	The c.1513C>T (p.R505W) alteration is located in exon 9 (coding exon 9) of the HMGCS2 gene. This alteration results from a C to T substitution at nucleotide position 1513, causing the arginine (R) at amino acid position 505 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000402158	SCV004807002	uncertain significance	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2024-03-26	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004691134	SCV005186856	uncertain significance	not provided		criteria provided, single submitter	not provided