Submissions for variant NM_000162.5(GCK):c.1322C>G (p.Ser441Trp)

dbSNP: rs1286804191

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003313230	SCV004012134	pathogenic	Monogenic diabetes	2023-06-25	reviewed by expert panel	curation	The c.1322C>G variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Trp)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; PMID: 25665835). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ser441Trp has RAI=0.11, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 19884385). This variant was identified in 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 27420379, 25665835, 19884385, 17573900, 16965331, 11508276, internal lab contributors). In summary, 1322C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PP3, PP4_Moderate, PS3, PS4.
GeneDx	RCV001776634	SCV002013337	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrate greatly reduced enzyme activity compared to wildtype (PMID: 19884385); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27420379, 25665835, 11508276, 17573900, 14517946, 28726111, 16965331, 19884385)
Revvity Omics, Revvity	RCV001776634	SCV002018417	likely pathogenic	not provided	2019-09-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401708	SCV004103953	pathogenic	GCK-related disorder	2023-10-03	criteria provided, single submitter	clinical testing	The GCK c.1322C>G variant is predicted to result in the amino acid substitution p.Ser441Trp. This variant has been reported in multiple individuals with maturity-onset diabetes of the young (see for example, Figure 1, Massa et al. 2001. PubMed ID: 11508276; Table 1, Estalella et al. 2007. PubMed ID: 17573900; Oriola et al. 2015. PubMed ID: 25665835) and in multiple individuals with impaired fasting glucose (Figure 1, Barbetti et al. 2009. PubMed ID: 19884385; Table 2, Aloi et al. 2017. PubMed ID: 28726111). An in vitro experimental study shows this variant has greatly reduced enzyme activity compared to wildtype (Table 2, Barbetti et al. 2009. PubMed ID: 19884385). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV005250198	SCV005900308	pathogenic	Maturity onset diabetes mellitus in young	2025-02-06	criteria provided, single submitter	clinical testing	This sequence change in GCK is predicted to replace serine with tryptophan at codon 441, p.(Ser441Trp). The serine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the second hexokinase domain. There is a large physicochemical difference between serine and tryptophan. This variant is absent from the population database gnomAD v4.1. ClinVar contains an entry for this variant (Variation ID: 1320655) This variant has been reported in at least 6 probands with maturity-onset diabetes of the young (MODY) and has been shown to segregate with disease in a several relatives of a family affected by MODY (PMID: 16965331, 17573900, 19884385, 27420379; Royal Melbourne Hospital). Kinetic analysis of this variant showed low enzymatic activity compared to wild-type GCK (PMID: 19884385). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.97). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PP1_Moderate, PP3_Strong, PS3_Supporting, PS4_Moderate.