Submissions for variant NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

dbSNP: rs751279776

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000992055	SCV001144023	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with MODY in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8325892, 30257192)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248939	SCV001422718	pathogenic	Maturity-onset diabetes of the young type 2	2020-01-22	criteria provided, single submitter	curation	The p.Ala188Thr variant in GCK has been reported in 2 homozygous Egyptian individuals and 2 heterozygous Egyptian individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected relatives from 1 family (DOI: 10.1007/s13410-018-0658-6), and has been identified in 0.005% (1/18390) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs751279776). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. 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 vitro functional studies provide some evidence that the p.Ala188Thr variant may slightly impact protein function (PMID: 30257192). However, these types of assays may not accurately represent biological function. The p.Ala188Thr variant is located in a region of GCK that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30257192). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease and more affected individuals with the variant than expected. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PM1_Supporting, PS3_Supporting (Richards 2015).
Genetic Services Laboratory, University of Chicago	RCV000992055	SCV002067433	pathogenic	not provided	2020-12-08	criteria provided, single submitter	clinical testing	This sequence change has been previously described in multiple patients and families with GCK-related MODY (PMID: 8314448, 30257192, 14517956, 29207974 and 20337973). This particular sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs751279776). Experimental studies have indicated reduced enzymatic activity and protein stability for this sequence change (PMID: 30257192). The p.Ala188Thr change affects a highly conserved amino acid residue located in a Hexokinase domain of the GCK protein that is known to be functional. The p.Ala188Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic.
Geisinger Clinic, Geisinger Health System	RCV001248939	SCV002562179	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
3billion	RCV001248939	SCV002573171	pathogenic	Maturity-onset diabetes of the young type 2	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 30257192). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000804849). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 30257192). Different missense changes at the same codon (p.Ala188Glu, p.Ala188Gly, p.Ala188Pro, p.Ala188Val) have been reported to be associated with GCK -related disorder (ClinVar ID: VCV000036229 / PMID: 12050210 , 16965331 , 19790256 , 31968686). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000992055	SCV003439965	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 8325892, 30257192). 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. ClinVar contains an entry for this variant (Variation ID: 804849). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8314448, 12050210, 28170077, 30257192). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs751279776, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 188 of the GCK protein (p.Ala188Thr).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017770	SCV004848488	pathogenic	Maturity onset diabetes mellitus in young	2020-11-06	criteria provided, single submitter	clinical testing	The p.Ala187Thr (also known as p.Ala188Thr) variant in GCK has been reported in at least 11 individuals with maturity onset diabetes of the young (MODY) and segregated with disease in 7 affected individuals from at least 2 families (Bansal 2017 PMID: 29207974, Santan 2017 PMID: 28170077, Capuan 2012 PMID: 22761713, Feigerlova 2006 PMID: 16602010, Mantovani 2003 PMID: 12955723, Barrio 2002 PMID: 12050210, Pruhova 2010 PMID: 20337973, Shimada 1993 PMID: 8314448, Thomson 2003 PMID: 14517956). It has also been identified in 0.005438% (1/18390) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 804849). 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 vitro functional studies provide some evidence that this variant impacts protein function (George 2014 PMID: 24578721, Takeda 1993 PMID: 8325892); however, these types of assays may not accurately represent biological function. Additional variants, resulting in different amino acid changes at the same position (e.g., p.A188G, p.A188P, p.A188V) have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.
GeneDx	RCV000992055	SCV005202001	pathogenic	not provided	2024-02-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced enzymatic activity, decreased thermal stability, and decreased affinity for glucose compared to wildtype (PMID: 8325892, 30257192); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20337973, 16602010, 8314448, 30257192, 24578721, 14517956, 12050210, 19790256, 22761713, 12955723, 34108472, 36208030, 31216801, 7806138, 34440516, 35592779, 36227502, 29207974, 36836406, 36504295, 36257325, 8325892, 28170077)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001248939	SCV005417496	pathogenic	Maturity-onset diabetes of the young type 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5+PS3_Supporting+PS4_Supporting+PP4+PP1_Strong