ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.704A>G (p.His235Arg)

gnomAD frequency: 0.00001  dbSNP: rs990313450
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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 RCV001280065 SCV003517751 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 235 of the HMGCL protein (p.His235Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with HMGCL-related conditions. 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 RCV003490167 SCV004241033 uncertain significance not specified 2023-12-13 criteria provided, single submitter clinical testing Variant summary: HMGCL c.704A>G (p.His235Arg) results in a non-conservative amino acid change located in the Pyruvate carboxyltransferase (IPR000891) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251422 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.704A>G has been reported in the literature in at least one compound heterozygous individual affected with HMG-CoA Lyase Deficiency (e.g. Roland_2017). These report(s) do not provide unequivocal conclusions about association of the variant with HMG-CoA Lyase Deficiency. 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: 28396157). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001280065 SCV001467213 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2020-08-28 no assertion criteria provided clinical testing

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