Submissions for variant NM_005518.4(HMGCS2):c.1522G>A (p.Val508Ile)

gnomAD frequency: 0.00207  dbSNP: rs76773981

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000342894	SCV000347900	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756249	SCV000883999	uncertain significance	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The HMGCS2 c.1522G>A; p.Val508Ile variant (rs76773981), to our knowledge, is not reported in the medical literature; however it is listed in ClinVar as uncertain (Variation ID: 292327). This variant is found in the general population with an overall allele frequency of 0.19% (526/276,942 alleles, including 1 homozygotes) in the Genome Aggregation Database. The valine at codon 508 is moderately conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Taken together, based on the available evidence, this the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000342894	SCV001100836	likely benign	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2024-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000756249	SCV001780062	likely benign	not provided	2019-07-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000756249	SCV002496909	likely benign	not provided	2022-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003910056	SCV004721369	benign	HMGCS2-related disorder	2019-11-25	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).