Submissions for variant NM_000162.5(GCK):c.572G>A (p.Arg191Gln)

dbSNP: rs886042610

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222471	SCV005040698	pathogenic	Monogenic diabetes	2024-04-19	reviewed by expert panel	curation	The c.605T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 202 (p.(Met202Arg)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.873, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 39 unrelated individuals with hyperglycemia (PS4; PMID: 30259503, 29927023, 29510678, 29207974, 29056535, 27256595, 25953829, 25555642, 24918535, 20337973, 19309449, 11508276, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three-generation, dominant family history of diabetes or hyperglycemia in a family not used for PP1) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 13 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Another missense variant, c.571C>T p.(Arg191Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Arg191Gln) (PM5_Supporting). In summary, c.572G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM2_Supporting, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting.
Athena Diagnostics	RCV000711776	SCV000842172	likely pathogenic	not provided	2019-09-26	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. This variant has been found in multiple unrelated patients that meet standard diagnostic criteria for the relevant disease. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.
GeneDx	RCV000711776	SCV001782913	pathogenic	not provided	2024-12-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 25555642, 33852230, 11508276, 27256595, 24918535, 20337973, 19790256, 22060211, 16444761, 19309449, 24804978, 29510678, 29056535, 29207974, 31957151, 38054414, 34373539, 35228227, 36504295, 36257325, 35472491)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711776	SCV002138629	pathogenic	not provided	2023-11-19	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 191 of the GCK protein (p.Arg191Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 16444761, 27256595, 29510678, 30259503). ClinVar contains an entry for this variant (Variation ID: 283358). 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 not expected to disrupt GCK protein function with a negative predictive value of 80%. This variant disrupts the p.Arg191 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23295292, 27269892). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222471	SCV002500417	pathogenic	Monogenic diabetes	2022-03-16	criteria provided, single submitter	clinical testing	Variant summary: GCK c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251110 control chromosomes (gnomAD). c.572G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes and the variant seggregated with the disease (example: Pruhova_2010, Codner_2009, Codner_2006, and Massa_2001). Another two variants affecting the same amino acid residue (p.R191L, p.R191W) are associated with MODY in HGMD. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Geisinger Clinic, Geisinger Health System	RCV002285302	SCV002562182	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PP3, PP2, PM2, PS4, PP1_Strong, PP4_Moderate, PM5_Supporting
Ambry Genetics	RCV002347992	SCV002650655	pathogenic	Maturity onset diabetes mellitus in young	2022-10-31	criteria provided, single submitter	clinical testing	The p.R191Q pathogenic mutation (also known as c.572G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described in the heterozygous state in several unrelated individuals with maturity-onset diabetes of the young (MODY), type 2 (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Codner E et al. Pediatr Diabetes, 2009 Sep;10:382-8; Codner E et al. Diabetes Metab Res Rev;22:348-55; Fulcoli FG et al. Nat Commun, 2016 06;7:11688; Aykut A et al. Gene, 2018 Jan;641:186-189; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172; Massa O et al. Diabetologia, 2001 Jul;44:898-905; Li X et al. BMC Pediatr, 2018 03;18:101; Al-Kandari H et al. Sci Rep, 2021 08;11:16060). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is expected to be causative of maturity-onset diabetes of the young (MODY), type 2 and permanent neonatal diabetes; however, its clinical significance for GCK-related neonatal hyperinsulinemic hypoglycemia is unclear.
Eurofins Ntd Llc (ga)	RCV000711776	SCV000335392	uncertain significance	not provided	2015-09-21	flagged submission	clinical testing