Submissions for variant NM_005518.4(HMGCS2):c.634G>A (p.Gly212Arg)

gnomAD frequency: 0.00026  dbSNP: rs137852638

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000009841	SCV000347911	likely pathogenic	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	The HMGCS2 c.634G>A (p.Gly212Arg) missense variant has been reported in three studies in which it is found in a compound heterozygous state in a total of three individuals with HMGCS deficiency (Aledo et al. 2001; Zschocke et al. 2002; Pitt et al. 2015). The variant was absent from 200 control chromosomes but is reported at a frequency of 0.00038 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in CHO-K1 cells demonstrated that the variant resulted in no detectable HMGS activity (Aledo et al. 2001) and failed to produce a soluble protein as detected by Western blotting (Ramos et al. 2013). Structural studies showed that the Gly212 residue is tightly packed in the thiolase fold, and that substitution with an arginine residue may result in steric and electrostatic clashes (Shafqat et al. 2010). Based on the evidence, the p.Gly212Arg variant is classified as likely pathogenic for 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS) deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000498667	SCV000589479	pathogenic	not provided	2024-04-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: lack of production of a soluble protein and no residual 3-hydroxy-3-methylglutaryl-CoA synthase enzyme activity compared to wild type (PMID: 11479731, 23751782); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23751782, 20346956, 25511235, 11479731, 31980526, 31589614, 32905056, 12072887)
SIB Swiss Institute of Bioinformatics	RCV000009841	SCV000883153	likely pathogenic	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for 3-hydroxy-3-methylglutaryl-coa synthase-2 deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. PM3 => For recessive disorders, detected in trans with a pathogenic variant. PM2-Supporting => PM2 downgraded in strength to Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000009841	SCV002109453	pathogenic	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 212 of the HMGCS2 protein (p.Gly212Arg). This variant is present in population databases (rs137852638, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (PMID: 11479731, 12072887, 25511235). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 9259). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HMGCS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 11479731). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000009841	SCV004810033	pathogenic	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000009841	SCV000030062	pathogenic	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	2001-07-01	no assertion criteria provided	literature only