Submissions for variant NM_000162.5(GCK):c.737G>C (p.Gly246Ala)

dbSNP: rs1583596522

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003446565	SCV004174237	likely pathogenic	Monogenic diabetes	2023-12-02	reviewed by expert panel	curation	The c.737G>C variant in the glucokinase gene, GCK, causes an amino acid change of glycine to alanine at codon 246 (p.(Gly246Ala)) 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 0.839, 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 was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID:27256595, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate, PMID:27256595). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). Another missense variant, c.736G>A p.Gly246Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly246Ala (PM5_Supporting). In summary, c.737G>C meets the criteria to be classified as likely 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, PS4_Moderate, PP1_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting.
Athena Diagnostics	RCV000992062	SCV001144033	uncertain significance	not provided	2019-08-08	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002382224	SCV002605106	uncertain risk allele	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1583596522 in MODY, yet.
Ambry Genetics	RCV002382224	SCV002672389	uncertain significance	Maturity onset diabetes mellitus in young	2017-01-20	criteria provided, single submitter	clinical testing	The p.G246A variant (also known as c.737G>C), located in coding exon 7 of the GCK gene, results from a G to C substitution at nucleotide position 737. The glycine at codon 246 is replaced by alanine, an amino acid with similar properties. This variant was identified in an overweight individual diagnosed with diabetes at 9 years old and treated by diet; this alteration was inherited from this individual's mother with fasting hyperglycemia and reported as a variant of uncertain significance (Haliloglu B et al. Clin. Endocrinol. (Oxf), 2016 Sep;85:393-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000992062	SCV005835117	likely pathogenic	not provided	2024-06-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 246 of the GCK protein (p.Gly246Ala). 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: 27256595; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 804856). 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.Gly246 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19790256, 32533152, 33852230; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.