Submissions for variant NM_000162.5(GCK):c.781G>A (p.Gly261Arg)

dbSNP: rs104894008

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325940	SCV004032083	pathogenic	Monogenic diabetes	2023-08-12	reviewed by expert panel	curation	The c.781G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 261 (p.(Gly261Arg)) 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 0.914, which is greater than the MDEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the "Other" subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF less than or equal to 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 38 unrelated individuals with diabetes (PS4; PMIDs: 29417725, 33324081, 21518409, 25015100, 22611063, 17573900, internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 30 informative meioses in 18 families (PP1_Strong; PMID 33324081, 21518409, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (PS2; internal lab contributors). This variant has been detected in at least 2 individuals with neonatal diabetes who were both homozygous for the variant, confirmed in trans (PM3: PMID 33324081, 25015100, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Gly261Arg variant has a relative activity index (RAI) of 0.02, which is less than the MDEP VCEP threshold of 0.50 (PMID: 19903754). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetews. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2.
GeneDx	RCV000426797	SCV000513127	pathogenic	not provided	2022-11-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with the presence of the variant causing significantly decreased Glucokinase activity in comparison to wild-type (Gidh-Jain et al., 1993; Raimondo et al., 2014); 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 often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 9049484, 30191644, 21521320, 22611063, 10525657, 25015100, 8446612, 1502186, 17573900, 27167055, 1464666, 10694920, 30663027, 21518409, 22761713, 8168652, 19903754, 34440516, 34496959)
Athena Diagnostics	RCV000426797	SCV000613458	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Heterozygous individuals with this variant presented with clinical features of MODY, while homozygous individuals presented with permanent neonatal diabetes mellitus. This variant associates with MODY in multiple families. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in reduced kinase activity (PMID: 8446612, 19903754, 10525657).
Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile	RCV000017515	SCV000899100	pathogenic	Maturity-onset diabetes of the young type 2	2019-04-01	criteria provided, single submitter	clinical testing	Using next-generation sequencing, we found the heterozygous variant in a patient under suspect of MODY. -Mean coverage: 122X; 98.4% of target-regions at 20X
Invitae	RCV000426797	SCV002139794	pathogenic	not provided	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 261 of the GCK protein (p.Gly261Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal dominant GCK-related conditions (PMID: 1502186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16135). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 10525657). For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV000017515	SCV002562193	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP2, PP3, PP4_Moderate, PS3_Moderate, PM3, PP1_Strong, PS4, PS2
Ambry Genetics	RCV001507008	SCV002673352	pathogenic	Maturity onset diabetes mellitus in young	2020-08-27	criteria provided, single submitter	clinical testing	The p.G261R pathogenic mutation (also known as c.781G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 781. The glycine at codon 261 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and families with a clinical diagnosis of maturity-onset diabetes of the young (MODY), and has been shown to segregate with disease (Velho G et al. Diabetologia, 1997 Feb;40:217-24; Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Yorifuji T et al. Pediatr Diabetes, 2012 Feb;13:26-32). In one family, the proband was homozygous for p.G261R and presented with permanent neonatal diabetes mellitus; elevated fasting glucose was detected in four heterozygous family members: two sisters, the father with a history of diabetes, and the mother with a history of gestational diabetes (Bennett K et al. Pediatr Diabetes, 2011 May;12:192-6). In addition, functional studies have shown that p.G261R mutant GCK has significantly reduced enzymatic activity compared to wild-type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Beer NL et al. Diabetes Care, 2012 Jul;35:1482-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV000017515	SCV002761776	likely pathogenic	Maturity-onset diabetes of the young type 2	2021-12-30	criteria provided, single submitter	clinical testing	The GCK c.781G>A variant is classified as Likely Pathogenic (PS3, PM2, PP3) The GCK c.781G>A variant is a single nucleotide change in exon 7/10 of the GCK gene, which is predicted to change the amino acid glycine at position 261 in the protein to arginine. This variant is absent from population databases (PM2). Well-established functional studies show a deleterious effect of this variant ( Gidh-Jain et al. (PMID:8446612) ) (PS3). Please note this variant has been previously reported in the literature as: NM_0001354800.1: c.781G>A, p.Gly261Arg.
OMIM	RCV000017515	SCV000037787	pathogenic	Maturity-onset diabetes of the young type 2	1992-08-15	no assertion criteria provided	literature only
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV003445078	SCV004174115	pathogenic	Maturity-onset diabetes of the young type 3		no assertion criteria provided	clinical testing