ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.1262T>G (p.Phe421Cys)

dbSNP: rs1652723339
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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 RCV001234326 SCV001406966 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2023-07-12 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of HMG-CoA synthase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 421 of the HMGCS2 protein (p.Phe421Cys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 960746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HMGCS2 protein function. 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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