Submissions for variant NM_000162.5(GCK):c.1133C>A (p.Ala378Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003445468	SCV004174248	pathogenic	Maturity-onset diabetes of the young type 2	2023-11-22	reviewed by expert panel	curation	The c.1133C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to aspartic acid at codon 378 (p.(Ala378Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, 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 5-6 unrelated individuals with hyperglycemia (PS4; internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of diabetes or hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.1133C>T (p.Ala378Val) and c.1132G>A (p.Ala378Thr) have been interpreted as pathogenic by the ClinGen MDEP, and p.Ala378Asp has an greater Grantham distance than p.Ala378Val and p.Ala378Thr (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_moderate, PM5_Strong.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479526	SCV004223414	pathogenic	Monogenic diabetes	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1133C>A (p.Ala378Asp) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Other variants located at the same codon, namely c.1133C>G (p.Ala378Gly); c.1133C>T (p.Ala378Val); c.1132C>A (p.Ala378Thr) have been reported with P/LP classifications, supporting a critical relevance of this Alanine residue to GCK protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234946 control chromosomes. c.1133C>A has been reported in the literature in individuals affected with features and clinical criteria of GCK-associated Monogenic Diabetes (example, Colclough_2022, Saint-Martin_2022, Mirshahi_2022, Osbak_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34789499, 36257325, 19790256, 34556497). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.