ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.698A>G (p.His233Arg)

gnomAD frequency: 0.00004  dbSNP: rs727503963
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000153365 SCV000202849 pathogenic not provided 2014-01-23 criteria provided, single submitter clinical testing
Counsyl RCV000665316 SCV000789416 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-02-07 criteria provided, single submitter clinical testing
Invitae RCV000665316 SCV000818257 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 233 of the HMGCL protein (p.His233Arg). This variant is present in population databases (rs727503963, gnomAD 0.002%). This missense change has been observed in individual(s) with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (PMID: 9784232, 14518825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167180). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HMGCL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCL function (PMID: 8798725, 16330550). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000665316 SCV000893291 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665316 SCV000919521 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The HMGCL c.698A>G (p.His233Arg) variant involves the alteration of a conserved nucleotide that is located in the Pyruvate carboxyltransferase (InterPro) and is found in the active site required for Mg2+ binding (Fu_2006). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/277164 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic HMGCL variant (0.0007071). The variant is reported in the literature as a homozygous and compound heterozygous allele in multiple patients, and functional studies show undetectable enzyme activity in the fibroblasts and lymphocytes of patients (Roberts_1996, Pospisilova_2003). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx RCV000153365 SCV002504205 pathogenic not provided 2022-04-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant is associated with less than 1% 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (Roberts et al., 1996); This variant is associated with the following publications: (PMID: 19177531, 16330550, 9784232, 14518825, 17692550, 15308132, 22847177, 9463337, 8798725)
PreventionGenetics, part of Exact Sciences RCV003415999 SCV004117516 pathogenic HMGCL-related disorder 2023-03-15 criteria provided, single submitter clinical testing The HMGCL c.698A>G variant is predicted to result in the amino acid substitution p.His233Arg. This variant has previously been reported to be causative for HMG-CoA lyase deficiency (Pospísilová E et al 2003. PubMed ID: 14518825; Mitchell GA et al 1998. PubMed ID: 9463337; Menao S et al 2009. PubMed ID: 19177531). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24134677-T-C). This variant is interpreted as pathogenic.
Genome-Nilou Lab RCV000665316 SCV004173950 likely pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000665316 SCV004199886 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-10-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV001831955 SCV002094155 pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-12-14 no assertion criteria provided clinical testing

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