Submissions for variant NM_000162.5(GCK):c.793G>A (p.Glu265Lys)

dbSNP: rs104894011

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000516510	SCV000613461	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced the enzyme's thermal stability and activity (PMID: 18322640, 16173921).
Genetic Services Laboratory, University of Chicago	RCV000516510	SCV002072116	pathogenic	not provided	2017-09-18	criteria provided, single submitter	clinical testing
Invitae	RCV000516510	SCV002245927	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 265 of the GCK protein (p.Glu265Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 16173921, 17573900, 18322640, 18382660, 20337973, 23295287, 25414397). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447419). 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%. Experimental studies have shown that this missense change affects GCK function (PMID: 16173921, 25414397). This variant disrupts the p.Glu265 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 19564454), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV002285350	SCV002562195	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PS4_Moderate, PP4, PP2, PS3
Fulgent Genetics, Fulgent Genetics	RCV002490882	SCV002780923	pathogenic	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2022-05-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000516510	SCV004169119	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrate a damaging effect on enzymatic activity and may affect protein stability (PMID: 16173921, 18322640); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter 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: 23295287, 19790256, 25414397, 16173921, 17573900, 18322640, 28012402, 20337973, 35472491, 18382660)