Submissions for variant NM_000162.5(GCK):c.661G>A (p.Glu221Lys)

dbSNP: rs193922317

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003155041	SCV004697921	pathogenic	Monogenic diabetes	2024-02-28	reviewed by expert panel	curation	The c.661A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 221 (p.(Glu221Lys)) 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 0.789, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein's function by the ClinGen MDEP. This variant was identified in 4 unelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; PMID: 23295292, internal lab contributors). This variant has been identified in 25 unrelated individuals with hyperglycemia and segregated with the phenotype, with 17 informative meioses in at least 7 families (PS4, PP1_Strong; PMIDs: 10694920, 12955723, 31658956, 34462253, 35592779, 35733065, 23295292, and 30592380). A relative activity index (RAI) was calculated for this variant but the wild type parameters are outside of MDEP's recommendations; therefore, this data cannot be used towards PS3 (PMID: 30592380). In summary, c.661A>G 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, approved 8/11/2023): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155041	SCV000052559	pathogenic	Monogenic diabetes	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: GCK c.661G>A (p.Glu221Lys) results in a conservative amino acid change in 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 251548 control chromosomes (gnomAD, Guazzini_1998). c.661G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes (Guazzini_1998, Mantovani_2003, Caetano_2012, Wang_2019), and has been observed segregating with disease within families (Guazzini_1998, Caetano_2012, Wang_2019). These data indicate that the variant is very likely to be associated with disease. Wang_2019 found that the relative activity level of the variant protein was 47%. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV000711781	SCV000842178	pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing
Geisinger Clinic, Geisinger Health System	RCV000029904	SCV002562188	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP1_Strong, PS4, PP4_Moderate, PP2, PS3
Ambry Genetics	RCV002371787	SCV002667254	pathogenic	Maturity onset diabetes mellitus in young	2017-04-18	criteria provided, single submitter	clinical testing	The p.E221K pathogenic mutation (also known as c.661G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 661. The glutamic acid at codon 221 is replaced by lysine, an amino acid with similar properties. This mutation has been described in multiple individuals of Italian descent with impaired glucose tolerance or maturity-onset diabetes of the young (MODY) (Guazzini B et al. Hum. Mutat., 1998;12:136; Massa O et al. Diabetologia, 2001 Jul;44:898-905; Mantovani V et al. Hum. Mutat., 2003 Oct;22:338). Furthermore, in a Brazilian family with MODY, this mutation co-segregated with hyperglycemia and was absent in normoglycemic family members (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711781	SCV003439931	pathogenic	not provided	2023-12-13	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 221 of the GCK protein (p.Glu221Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 23295292, 26226118, 31216263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36241). 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: 30592380). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.