Submissions for variant NM_000162.5(GCK):c.1228G>C (p.Gly410Arg)

dbSNP: rs2128819136

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004527442	SCV005040680	pathogenic	Monogenic diabetes	2024-04-28	reviewed by expert panel	curation	The c.1228G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 410 (p.(Gly410Arg)) 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 0.989, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual 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). Two other missense variants, c.1229G>A p.Gly410Asp and c.1228G>A p.Gly410Ser, have been interpreted as pathogenic by the ClinGen MDEP, and p.Gly410Arg has a greater Grantham distance than p.Gly410Asp and p.Gly410Ser (PM5_Strong). In summary, c.1228G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM1, PP2, PP3, PM2_Supporting, PM5_Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001977269	SCV002264760	uncertain significance	not provided	2021-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 410 of the GCK protein (p.Gly410Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 28323911; Invitae). 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. This variant disrupts the p.Gly410 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 30977832), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.