ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.1220T>C (p.Ile407Thr)

gnomAD frequency: 0.00002  dbSNP: rs766898190
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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 RCV001908833 SCV002171336 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2022-02-24 criteria provided, single submitter clinical testing The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 29597274). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with clinical features of HMG-CoA synthase deficiency (PMID: 25511235). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 407 of the HMGCS2 protein (p.Ile407Thr).

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