ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.346C>T (p.Arg116Cys)

gnomAD frequency: 0.00002  dbSNP: rs200607527
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185972 SCV000238930 uncertain significance not provided 2019-04-19 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000697575 SCV000826195 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 116 of the HMGCS2 protein (p.Arg116Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200607527, ExAC 0.004%). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 203779). 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 C15"). 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.

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