Submissions for variant NM_000162.5(GCK):c.1207C>G (p.Arg403Gly)

dbSNP: rs193922271

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234925	SCV000052505	uncertain significance	not specified	2023-05-04	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1207C>G (p.Arg403Gly) results in a non-conservative amino acid change located in the C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239820 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1207C>G has been reported in the literature in at least one individual affected with diabetes, however without strong evidence for causality (e.g., Billings_2022). This report does not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 36208030). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000029850	SCV001423043	uncertain significance	Maturity-onset diabetes of the young type 2	2020-01-22	criteria provided, single submitter	curation	The p.Arg403Gly variant in GCK has not been previously reported in individuals with maturity-onset diabetes of the young type 2 and was absent from large population studies. This variant has been reported in ClinVar (VariationID: 36187) as likely pathogenic by Integrated Genetics Laboratory. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg403Gly variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015).
Athena Diagnostics Inc	RCV001288976	SCV001476451	uncertain significance	not provided	2020-10-06	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000029850	SCV002605078	likely risk allele	Maturity-onset diabetes of the young type 2	2024-02-21	criteria provided, single submitter	research	Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs193922271 in MODY, yet.This variant is a potent moderate impact, deleterious variant with a CADD score of 23.9. This gene is found to be frequently associated with MODY as per recent evidence as well, with sufficient scientific evidence to support the reported classification. Heterozygous mutations in the GCK gene cause maturity-onset diabetes of the young (MODY), characterized by mild hyperglycemia often detected later in life. GCK-MODY exhibits dominantly inherited fasting hyperglycemia due to variants in the glucokinase gene, with over 600 mutations identified. Homozygous mutations result in severe permanent neonatal diabetes. Additionally, activating GCK mutations can lead to hypoglycemia.
Ambry Genetics	RCV002345255	SCV002647849	uncertain significance	Maturity onset diabetes mellitus in young	2017-09-28	criteria provided, single submitter	clinical testing	The p.R403G variant (also known as c.1207C>G), located in coding exon 9 of the GCK gene, results from a C to G substitution at nucleotide position 1207. The arginine at codon 403 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.