ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.104G>T (p.Arg35Met)

dbSNP: rs751101083
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000799471 SCV000939135 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-08-12 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with HMGCS2-related disease. This variant is present in population databases (rs751101083, ExAC 0.01%). This sequence change replaces arginine with methionine at codon 35 of the HMGCS2 protein (p.Arg35Met). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and methionine. This variant also falls at the last nucleotide of exon 1 of the HMGCS2 coding sequence, which is part of the consensus splice site for this exon.

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