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

gnomAD frequency: 0.00004  dbSNP: rs121964997

Total submissions: 15

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	2024-03-12	criteria provided, single submitter	clinical testing
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