ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.73C>G (p.Pro25Ala)

gnomAD frequency: 0.00016  dbSNP: rs144744634
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185971 SCV000238929 likely benign not specified 2013-11-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000647361 SCV000769154 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 25 of the HMGCS2 protein (p.Pro25Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs144744634, ExAC 0.08%). 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: 203778). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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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