ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.1127C>T (p.Thr376Ile)

gnomAD frequency: 0.00002  dbSNP: rs772359110
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001917950 SCV002169761 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2022-06-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 376 of the HMGCS2 protein (p.Thr376Ile). This variant is present in population databases (rs772359110, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV004041719 SCV004884693 uncertain significance Inborn genetic diseases 2023-10-28 criteria provided, single submitter clinical testing The c.1127C>T (p.T376I) alteration is located in exon 6 (coding exon 6) of the HMGCS2 gene. This alteration results from a C to T substitution at nucleotide position 1127, causing the threonine (T) at amino acid position 376 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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