ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.787T>C (p.Ser263Pro) (rs193922331)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029921 SCV000052576 likely pathogenic Maturity-onset diabetes of the young, type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Genetic Services Laboratory,University of Chicago RCV000117135 SCV000151296 likely pathogenic Gestational diabetes 2013-11-04 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000517906 SCV000613460 likely pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing
GeneDx RCV000517906 SCV000779665 likely pathogenic not provided 2018-03-26 criteria provided, single submitter clinical testing The S263P variant has been published previously in association with MODY (Cao et al., 2002). The variant is observed in 1/14988 (0.0067%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). S263P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown S263P may result in reduced thermal stability or self-aggregation (Sagen et al., 2006; Fenner et al., 2011; Negahdar et al., 2012). Missense variants in nearby residues (G258S/R/C/D, A259T/V, G261R/E, G264S, E265K/V, L266V/Q, E268K) have been reported in the Human Gene Mutation Database in association with GCK-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic.
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000029921 SCV000882458 likely pathogenic Maturity-onset diabetes of the young, type 2 2017-06-09 criteria provided, single submitter clinical testing The c.787T>C variant in codon 263 (exon 7) of the glucokinase gene, GCK, results in the substitution of Serine to a Proline. The c.787T>C was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported to segregate with diabetes in a family whose clinical picture is consistent with Maturity-Onset Diabetes of the Young (MODY) (12442280). Functional analyses of this variant have demonstrated thermal instability, protein misfolding and aberrant dimerization (22820548;16731834). Additionally, multiple lines of computational evidence (SIFT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG criteria = PS3, PM2, PP1, PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826166 SCV000967704 likely pathogenic Maturity onset diabetes mellitus in young 2019-01-18 criteria provided, single submitter clinical testing The p.Ser262Pro variant in GCK has been reported in at least 3 individuals with suspicion for MODY and segregated with disease in at least 3 affected members of two families (Cao 2002, Sagen 2006, GeneDx personal communication). It has also been identified in 1/128844 European chromosomes by gnomAD (http://gnomad.broad and has been reported as likely pathogenic in ClinVar (Variation ID 36258). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. However, multiple in vitro functional studies suggest that this variant impacts protein function (Sag en 2006, Zelent 2011, Fenner 2011, Negahdar 2012, George 2014). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Ser262Pro variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PS4_Supporting.

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