ClinVar Miner

Submissions for variant NM_005518.3(HMGCS2):c.634G>A (p.Gly212Arg) (rs137852638)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498667 SCV000589479 pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing The G212R pathogenic variant has been reported previously in individuals with mitochondrial HMG-CoA synthasedeficiency (Aledo et al., 2001; Ramos et al., 2013). Expression studies in E. coli and in CHO cells found that theG212R variant did not produce a soluble protein and is associated with no residual 3-hydroxy-3- methylglutaryl-CoAsynthase enzyme activity in comparison to wild type (Aledo et al., 2001; Ramos et al., 2013). In summary, thisvariant is interpreted to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000009841 SCV000347911 likely pathogenic mitochondrial 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.
OMIM RCV000009841 SCV000030062 pathogenic mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2001-07-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000009841 SCV000883153 likely pathogenic mitochondrial 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.

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