Submissions for variant NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)

dbSNP: rs193922272

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001248969	SCV004012147	pathogenic	Monogenic diabetes	2023-06-26	reviewed by expert panel	curation	The c.1240A>G variant in the glucokinase gene, GCK, causes an amino acid change of lysine to glutamic acid at codon 414 (p.(Lys414Glu)) 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 resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.9279, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in seven unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; ClinVar ID 36188, PMID 18411240, internal lab contributors). The variant segregated with diabetes, with 5 informative meioses in three families with MODY (PP1_Strong; internal lab contributors). Additionally, one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributor). In summary, c.1240A>G meets the criteria to be classified as pathogenic by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PS4, PP4, PM1, PP2, PP3, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029851	SCV000052506	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 Inc	RCV000711759	SCV000842153	pathogenic	not provided	2020-01-14	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. The gain of a new splice site is predicted. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248969	SCV001422801	likely pathogenic	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Lys414Glu variant in GCK has been reported in at least one individual with Monogenic Diabetes (PMID: 8433729), and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36188). In vitro functional studies provide some evidence that the p.Lys414Glu variant may impact protein binding and activity (PMID: 21831042, 8325892, 10525657). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes Monogenic Diabetes (PMID: 17353190). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV003398573	SCV004105100	pathogenic	GCK-related condition	2023-11-17	criteria provided, single submitter	clinical testing	The GCK c.1240A>G variant is predicted to result in the amino acid substitution p.Lys414Glu. This variant has been reported in multiple individuals to be causative for maturity onset diabetes of the young (MODY) and/or hyperglycemia due to a decrease of glucokinase activity (Froguel et al. 1993. PubMed ID: 8433729; Takeda et al. 1993. PubMed ID: 8325892; Davis et al. 1999. PubMed ID: 10525657) Additionally, functional studies found this variant impacts GCK function (Pino et al. 2007. PubMed ID: 17353190; Zelent et al. 2011. PubMed ID: 21831042). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.