ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.805G>A (p.Ala269Thr)

gnomAD frequency: 0.00004  dbSNP: rs368688262
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001886179 SCV002156629 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 269 of the HMGCL protein (p.Ala269Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HMGCL-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 disruptive, 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.
GeneDx RCV002279977 SCV002568796 uncertain significance not provided 2022-02-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV001886179 SCV004172869 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2023-04-11 criteria provided, single submitter clinical testing

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