ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.244G>A (p.Val82Ile)

gnomAD frequency: 0.00007  dbSNP: rs538620811
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519900 SCV000617185 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing The V82I variant in the HMGCL gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 31/16496 (0.188%) alleles from individuals of South Asian background, in the ExAC dataset (Lek et al., 2016). The V82I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on currently available evidence, we interpret V82I as a variant of uncertain significance.
Invitae RCV001240005 SCV001412920 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2022-08-18 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 82 of the HMGCL protein (p.Val82Ile). This variant is present in population databases (rs538620811, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with HMGCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 449273). 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.
Genome-Nilou Lab RCV001240005 SCV004172681 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2023-04-11 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003979933 SCV004790154 likely benign HMGCL-related disorder 2022-04-15 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc. RCV001273184 SCV001455892 benign Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2019-10-28 no assertion criteria provided clinical testing

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