Submissions for variant NM_000162.5(GCK):c.1163G>A (p.Gly388Asp)

dbSNP: rs2096271482

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003446686	SCV004174247	pathogenic	Monogenic diabetes	2023-12-02	reviewed by expert panel	curation	The c.1163G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 388 (p.(Gly388Asp)) 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 0.871, 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 8 unrelated individuals with hyperglycemia (PS4; PMID:35737141, 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 negative antibodies) (PP4_Moderate, internal lab contributors). Another one of these individuals was identified as a de novo occurrence with confirmed parental relationships whose clinical picture was consistent with but not highly specific for GCK-hyperglycemia (PS2_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 3 families (PP1_Moderate; internal lab contributors). In summary, c.1163G>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, approved 8/11/2023): PS4, PP1_Moderate, PP4_Moderate, PS2_Moderate, PP2, PP3, PM2_Supporting.
Athena Diagnostics	RCV001288974	SCV001476449	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001288974	SCV001763942	likely pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 35737141, 19790256, 27106716)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288974	SCV002289353	uncertain significance	not provided	2021-04-09	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: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with maturity-onset diabetes of the young (MODY) (PMID: 19790256, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 388 of the GCK protein (p.Gly388Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002322180	SCV002605083	likely 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 rs2096271482 in MODY, yet.
Ambry Genetics	RCV002322180	SCV002631394	uncertain significance	Maturity onset diabetes mellitus in young	2020-01-13	criteria provided, single submitter	clinical testing	The p.G388D variant (also known as c.1163G>A), located in coding exon 9 of the GCK gene, results from a G to A substitution at nucleotide position 1163. The glycine at codon 388 is replaced by aspartic acid, an amino acid with similar properties. This alteration was detected in a family with Maturity-Onset Diabetes of the Young (MODY); however, no clinical details were provided (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003446686	SCV003800668	likely pathogenic	Monogenic diabetes	2023-11-30	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1163G>A (p.Gly388Asp) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 229364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1163G>A has been reported in the literature in at least 3 individuals affected with features of GCK-Maturity Onset Diabetes of the Young (Osbak_2009, Carmody_2016, Dusatkova_2022), however no further supporting evidence details (e.g. family history, and co-segregation) were provided. This was further corroborated by reports from the Clingen MODY expert panel identifying at-least ne additional affected individual meeting the clinical characteristics of GCK-MODY (personel correspondance). 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. However, several missense changes affecting nearby amino acids are reported in individual(s) affected with MODY, including L386V, A387E/T/V, V389A/D, I390V (HGMD), suggesting that this protein region might have clinical importance. The following publications have been ascertained in the context of this evaluation (PMID: 27106716, 35737141, 19790256, 28842611). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (VUS, n=3; likely pathogenic, n=1). Based on the evidence outlined above, the variant was re-classified as likely pathogenic.