ClinVar Miner

Submissions for variant NM_005518.3(HMGCS2):c.1499G>A (p.Arg500His) (rs137852639)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000009842 SCV000815145 uncertain significance mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 500 of the HMGCS2 protein (p.Arg500His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs137852639, ExAC 0.002%). This variant has been reported in combination with another HMGCS2 variant in an individual affected with HMG-CoA synthase deficiency (PMID: 11479731). ClinVar contains an entry for this variant (Variation ID: 9260). Experimental studies have shown that this missense change results in an HMGCS2 protein with no detectable HMG-CoA synthase activity (PMID: 23751782, 11479731). 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.
OMIM RCV000009842 SCV000030063 pathogenic mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2001-07-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000009842 SCV000787445 likely pathogenic mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-04-16 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for 3-hydroxy-3-methylglutaryl-coa synthase-2 deficiency, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. 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 (PMID:11479731).

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