Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003155293 | SCV004022344 | pathogenic | Monogenic diabetes | 2023-07-31 | reviewed by expert panel | curation | The c.608T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 203 (p.(Val203Ala)) 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 absent from gnomAD v2.1.1 (PM2_Supporting), and has been identified in at least 15 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; ClinVar ID: 585923, PMIDs: 9075802, 9000695, 8433729, 15841481,19790256). At least one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6%, antibody negative, and three-generation dominant family history of diabetes or hyperglycemia) (PP4_Moderate; PMID 15841481). This variant segregated with diabetes, with at least six informative meioses in five families with MODY (PP1_Strong; PMID:9075802, PMID:16059790). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, functional studies have determined that the c.608C>T variant has decreased catalytic activity as measured by a relative activity index (RAI) < 0.5 (PS3_Moderate; https://doi.org/10.1159/000079009). In summary, c.608C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 3/23/2023): PP1_Strong, PS4, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting). |
| Athena Diagnostics | RCV000711780 | SCV000842176 | pathogenic | not provided | 2022-07-20 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with MODY in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate the mutant protein has reduced catalytic activity and markedly reduced glucose affinity compared to wild-type proteins (PMIDs 8897004, 8446612, 10455021, 10525657). |
| Genetic Services Laboratory, |
RCV000711780 | SCV002067296 | pathogenic | not provided | 2020-03-02 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the GCK gene demonstrated a sequence change, c.608T>C, in exon 6 that results in an amino acid change, p.Val203Ala. This sequence change is absent from population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple families with GCK-MODY (PMIDs: 9075802, 8433729). In vitro functional analyses have demonstrated that the p.Val203Ala change results in decreased catalytic activity and increased glucose levels (PMIDs: 10455021, 8446612). The p.Val203Ala change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Val203Ala substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). |
| Labcorp Genetics |
RCV000711780 | SCV002241370 | pathogenic | not provided | 2024-11-30 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 203 of the GCK protein (p.Val203Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8433729, 9000695, 9075802, 15841481, 16059790). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585923). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 8446612, 8897004, 9078243, 10455021, 10525657). For these reasons, this variant has been classified as Pathogenic. |
| Clinical Genomics, |
RCV002352232 | SCV002605195 | 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 rs1562717053 in MODY, yet. | |
| Ambry Genetics | RCV002352232 | SCV002661009 | pathogenic | Maturity onset diabetes mellitus in young | 2019-11-20 | criteria provided, single submitter | clinical testing | The p.V203A pathogenic mutation (also known as c.608T>C), located in coding exon 6 of the GCK gene, results from a T to C substitution at nucleotide position 608. The valine at codon 203 is replaced by alanine, an amino acid with similar properties. This variant has been detected in unrelated individuals with maturity-onset diabetes of the young, and has been reported to segregate with disease in families (Froguel P et al. N. Engl. J. Med., 1993 Mar;328:697-702; Tappy L et al. Diabetes, 1997 Feb;46:204-8; Dussoix P et al. Diabetes, 1997 Apr;46:622-31; Toaima D et al. Hum. Mutat., 2005 May;25:503-4; Schnyder S et al. Swiss Med Wkly, 2005 Jun;135:352-6; Bennett JT et al. Mol. Genet. Metab., 2015 Mar;114:451-8). In addition, functional assays have indicated this variant to result in decreased enzyme activity compared to wild type (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Kesavan P et al. Biochem. J., 1997 Feb;322 ( Pt 1):57-63; Burke CV et al. Biochem. J., 1999 Sep;342 ( Pt 2):345-52). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Fulgent Genetics, |
RCV002499286 | SCV002810454 | pathogenic | Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1 | 2021-08-02 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155293 | SCV003844858 | pathogenic | Monogenic diabetes | 2023-02-03 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.608T>C (p.Val203Ala) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251452 control chromosomes (gnomAD). c.608T>C has been reported in the literature in multiple individuals affected with maturity-onset diabetes of the young (MODY) and was shown to segregate with disease within families (e.g. Froguel_1993, Dussoix_1997, Schnyder_2005). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to have decreased enzymatic activity compared to wild-type (Gidh-Jain_1993, Burke_1999, Davis_1999). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| ARUP Laboratories, |
RCV000711780 | SCV005877057 | pathogenic | not provided | 2024-07-11 | criteria provided, single submitter | clinical testing | The GCK c.608T>C; p.Val203Ala variant (rs1562717053) is reported in the literature in numerous individuals affected with features of maturity-onset diabetes of the young (MODY) and has been observed to segregate with disease in multiple families (Dussoix 1997, Froguel 1993, Mirshahi 2022, Schnyder 2005, Toaima 2005). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.946). Consistent with predictions, functional studies suggest the variant protein has significantly reduced catalytic activity compared to the wildtype protein (Burke 1999, Davis 1999, Gidh-Jain 1993). Based on available information, this variant is considered to be pathogenic. References: Burke CV et al. Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI). Biochem J. 1999 Sep 1;342 ( Pt 2)(Pt 2):345-52. PMID: 10455021. Davis EA et al. Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis. Diabetologia. 1999 Oct;42(10):1175-86. PMID: 10525657. Dussoix P et al. Diagnostic heterogeneity of diabetes in lean young adults: classification based on immunological and genetic parameters. Diabetes. 1997 Apr;46(4):622-31. PMID: 9075802. Froguel P et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993 Mar 11;328(10):697-702. PMID: 8433729. Gidh-Jain M et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID: 8446612. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Schnyder S et al. Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. Swiss Med Wkly. 2005 Jun 11;135(23-24):352-6. PMID: 16059790. Toaima D et al. Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). Hum Mutat. 2005 May;25(5):503-4. PMID: 15841481. |