Submissions for variant NM_000162.5(GCK):c.1339C>G (p.Arg447Gly)

dbSNP: rs193922281

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	RCV000029861	SCV000052516	likely pathogenic	Maturity-onset diabetes of the young type 2	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Athena Diagnostics	RCV001288979	SCV001476454	likely pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Segregation with disease in affected individuals from a single family.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288979	SCV002238454	pathogenic	not provided	2021-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glycine at codon 447 of the GCK protein (p.Arg447Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with autosomal recessive permanent neonatal diabetes mellitus and autosomal dominant MODY (PMID: 26587058; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36198). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002381268	SCV002691878	pathogenic	Maturity onset diabetes mellitus in young	2017-05-19	criteria provided, single submitter	clinical testing	The p.R447G pathogenic mutation (also known as c.1339C>G), located in coding exon 10 of the GCK gene, results from a C to G substitution at nucleotide position 1339. The arginine at codon 447 is replaced by glycine, an amino acid with dissimilar properties. This mutation was paternally inherited in two Brazilian double first cousins with permanent neonatal diabetes mellitus; each had a second, maternally inherited GCK alteration in trans. Their heterozygous fathers exhibited a maturity-onset diabetes of the young (MODY) phenotype (Esquiaveto-Aun AM et al. Diabetol Metab Syndr, 2015 Nov;7:101). In addition, another disease-causing alteration, p.R447Q, has been described in the same codon (Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001288979	SCV005325956	likely pathogenic	not provided	2024-01-26	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: 35228227, 34440516, 26587058)