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

gnomAD frequency: 0.00007  dbSNP: rs538620811

Total submissions: 5

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.
Labcorp Genetics (formerly Invitae), Labcorp	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
Natera, Inc.	RCV001273184	SCV001455892	benign	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003979933	SCV004790154	likely benign	HMGCL-related disorder	2022-04-15	no assertion criteria provided	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).