Submissions for variant NM_000162.5(GCK):c.1181G>T (p.Arg394Leu)

dbSNP: rs1235227560

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003318510	SCV004022345	uncertain significance	Monogenic diabetes	2023-07-16	reviewed by expert panel	curation	The c.1181G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 394 (p.(Arg394Leu)) of transcript NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and three generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). In summary, c.1181G>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002048713	SCV002310603	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 394 of the GCK protein (p.Arg394Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young type 2 (Invitae). ClinVar contains an entry for this variant (Variation ID: 1522625). 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 with a negative predictive value of 80%. This variant disrupts the p.Aeg394 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 28323911), 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.