ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)

gnomAD frequency: 0.00004  dbSNP: rs121964997
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000078342 SCV000110188 pathogenic not provided 2013-01-18 criteria provided, single submitter clinical testing
Counsyl RCV000012735 SCV000790225 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2017-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012735 SCV000919522 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2018-03-08 criteria provided, single submitter clinical testing Variant summary: HMGCL c.122G>A (p.Arg41Gln) results in a conservative amino acid change located in the Pyruvate carboxyltransferase of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant, c.122G>A, has been reported in the literature in multiple individuals affected with HMG-CoA Lyase Deficiency and has been indicated to be a Saudi Arabian founder mutation (Al-Sayed_2006) . These data indicate that the variant is very likely to be associated with disease. A clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Pathology and Clinical Laboratory Medicine, King Fahad Medical City RCV000012735 SCV000996288 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase criteria provided, single submitter clinical testing
Invitae RCV000012735 SCV001209850 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the HMGCL protein (p.Arg41Gln). This variant is present in population databases (rs121964997, gnomAD 0.01%). This missense change has been observed in individual(s) with 3HMG-CoA Lyase deficiency (PMID: 9463337, 14518825, 17173698, 28488182). ClinVar contains an entry for this variant (Variation ID: 11957). 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: 9463337, 15122894). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000012735 SCV001524522 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2020-06-08 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity RCV000012735 SCV002025005 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2021-03-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000012735 SCV002781040 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2022-03-30 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000012735 SCV004172770 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2023-04-11 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000012735 SCV004804931 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2024-03-17 criteria provided, single submitter research
OMIM RCV000012735 SCV000032970 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 1998-02-01 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000012735 SCV001132938 pathogenic Deficiency of hydroxymethylglutaryl-CoA lyase 2019-08-25 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000078342 SCV001739924 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000078342 SCV001957794 likely pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001831566 SCV002094168 pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-10-13 no assertion criteria provided clinical testing

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