ClinVar Miner

Submissions for variant NM_001166107.1(HMGCS2):c.1376G>C (p.Arg459Pro) (rs372079931)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522718 SCV000620878 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing The R501P variant in the HMGCS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R501P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R501P 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 that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000805374 SCV000945328 uncertain significance mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 501 of the HMGCS2 protein (p.Arg501Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HMGCS2-related disease. ClinVar contains an entry for this variant (Variation ID: 452101). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genomics, and Precision Dentistry Research Unit, Faculty of Dentistry, Chulalongkorn University RCV000805374 SCV001189983 likely pathogenic mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2020-03-15 criteria provided, single submitter research The patient is affected with Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) and harbors the compound heterozygous HMGCS2 mutations, c.1480C>T, p.Arg494* (SCV 001169710 assigned) inherited from his father and c.1502G>C, p.Arg501Pro from his mother.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.