ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.820G>A (p.Gly274Arg)

gnomAD frequency: 0.00001  dbSNP: rs1391067821
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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 RCV001908690 SCV002168998 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2022-04-26 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the HMGCL protein (p.Gly274Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with 3HMG-CoA lyase deficiency (PMID: 19932602). 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 disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587244 SCV005077241 uncertain significance not specified 2024-04-18 criteria provided, single submitter clinical testing Variant summary: HMGCL c.820G>A (p.Gly274Arg) results in a non-conservative amino acid change located in the Pyruvate carboxyltransferase domain (IPR000891) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.820G>A has been reported in the literature in an individual affected with HMG-CoA Lyase Deficiency (Pierron_2010). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19932602). ClinVar contains an entry for this variant (Variation ID: 1402741). Based on the evidence outlined above, the variant was classified as uncertain significance.

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