Submissions for variant NM_000162.5(GCK):c.802G>A (p.Glu268Lys)

dbSNP: rs1554335111

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003403215	SCV004102862	pathogenic	Monogenic diabetes	2023-10-05	reviewed by expert panel	curation	The c.802G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 268 (p.(Glu268Lys)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). 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 0.727, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.802G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting.
Athena Diagnostics Inc	RCV001851438	SCV000613463	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function.
Invitae	RCV001851438	SCV002132305	uncertain significance	not provided	2021-09-24	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 447420). This variant has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 19790256, 25555642). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 268 of the GCK protein (p.Glu268Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463707	SCV002605066	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 rs1554335111 in MODY, yet.
Revvity Omics, Revvity	RCV001851438	SCV003814504	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing