Submissions for variant NM_000162.5(GCK):c.544G>A (p.Val182Met)

dbSNP: rs587780345

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255191	SCV000321714	pathogenic	not provided	2023-05-19	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; Davis et al., 1999; Inoue et al., 2004); 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: 8446612, 19790256, 23771172, 29510678, 33852230, 31957151, 31968686, 10525657, 29056535, 29284910, 25695774, 15102714, 14517956, 21395678, 25494859, 8433729, 25082184, 20337973, 30191644, 33046911, 32792356, 33878173, 36208030, 18056790, 25306193, 25555642, 35177841)
Eurofins Ntd Llc (ga)	RCV000255191	SCV000337884	pathogenic	not provided	2015-11-25	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000255191	SCV000613440	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10525657)
Fulgent Genetics, Fulgent Genetics	RCV000763586	SCV000894425	pathogenic	Permanent neonatal diabetes mellitus; Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248908	SCV001422601	pathogenic	Maturity-onset diabetes of the young type 2	2020-01-22	criteria provided, single submitter	curation	The p.Val182Met variant in GCK has been reported in at least 9 individuals with maturity-onset diabetes of the young (MODY) type 2, segregated with disease in 4 affected relatives from 2 families (PMID: 29510678, 20337973, 21395678, 25082184, 23771172, 25306193, 25494859), and was absent from large population studies. Animal models in mice have shown that this variant causes MODY type 2 (15102714, 18056790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for MODY type 2 in an autosomal dominant manner based on the phenotype of mouse models being consistent with human disease, the increased prevalence of the variant in affected individuals, including relatives, compared to controls, and computational evidence. ACMG/AMP Criteria applied: PS3_PM2, PS4_moderate, PP3, PP1 (Richards 2015).
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000255191	SCV001448738	pathogenic	not provided	2018-02-20	criteria provided, single submitter	clinical testing
Invitae	RCV000255191	SCV002247025	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 182 of the GCK protein (p.Val182Met). 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: 8433729, 23771172, 30191644). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 129144). 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 GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 8446612, 10525657). For these reasons, this variant has been classified as Pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000255191	SCV002525647	pathogenic	not provided		criteria provided, single submitter	clinical testing	The c.544G>A (p.Val182Met, rs587780345) variant, located in exon 5 of the GCK gene, results in substitution of methionine for valine at amino acid position 182 of the protein. This variant has been reported as pathogenic in the literature and in ClinVar by multiple submitters (PMID: 8433729, 23771172, 30191644). Functional characterization has shown that this variant results in loss of glucokinase activity (PMID: 10525657). This variant is absent from large population controls (0 of >250,000 alleles tested; Genome Aggregation Database v2.1).
Geisinger Clinic, Geisinger Health System	RCV001248908	SCV002562177	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3
Ambry Genetics	RCV002345419	SCV002649099	pathogenic	Maturity onset diabetes mellitus in young	2023-01-20	criteria provided, single submitter	clinical testing	The p.V182M pathogenic mutation (also known as c.544G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 544. The valine at codon 182 is replaced by methionine, an amino acid with highly similar properties. This mutation was first reported to co-segregate with disease in two French MODY families (Froguel P et al. N. Engl. J. Med., 1993 Mar;328:697-702) and has subsequently been reported in multiple additional families (Costa A et al. Eur. J. Endocrinol., 2000 Apr;142:380-6; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Carmody D et al. Diabet. Med., 2015 Jun;32:e20-3). In addition, when expressed in E. coli and purified, mutant glucokinase carrying this mutation showed significantly decreased enzyme activity compared to wild-type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Davis EA et al. Diabetologia 1999 Oct;42(10):1175-86). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetic Services Laboratory, University of Chicago	RCV000117131	SCV002072032	pathogenic	Gestational diabetes	2020-09-11	no assertion criteria provided	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.544G>A, in exon 5 that results in an amino acid change, p.Val182Met. This sequence change has been previously described in several patients with GCK-related MODY (PMIDs: 8433729, 20337973, 23771172, 25494859 and 25555642). This sequence change is absent from the large population databases such as ExAC and gnoMAD (dbSNP rs587780345). The p.Val182Met change affects a highly conserved amino acid residue located in a domain of the GCK protein which is known to be functional (PMID: 8446612). The p.Val182Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL)