ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.71C>T (p.Thr24Ile)

gnomAD frequency: 0.00009  dbSNP: rs369221781
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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 RCV000706394 SCV000835439 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 24 of the HMGCS2 protein (p.Thr24Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs369221781, ExAC 0.02%). This variant has not been reported in the literature in individuals with HMGCS2-related disease. 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, 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.

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