ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.241G>A (p.Ala81Thr)

gnomAD frequency: 0.00019  dbSNP: rs151187711
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490124 SCV000577145 uncertain significance not provided 2017-04-10 criteria provided, single submitter clinical testing The A81T variant in the HMGCS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozyous state, the A81T variant is observed in 7/10406 (0.067%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The A81T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret A81T as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001065755 SCV001230736 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 81 of the HMGCS2 protein (p.Ala81Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs151187711, ExAC 0.07%). 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: 426647). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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