ClinVar

Description

Variant summary: The variant, GCK c.457C>T (p.Pro153Ser) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with an ExAC z score of 4.39 indicative of a gene relatively intolerant to benign missense variation (ACMG PP3, PP2). The variant was absent in 246268 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.457C>T has been reported in the literature in an individual affected with Maturity Onset Diabetes of the Young 2/Neonatal Diabetes Mellitus (Aloi_2017). However, this data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least one new report indicating its presence in an individual diagnosed with MODY or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until unequivocal co-segregation with disease in additional families/individuals with MODY2/NDM and functional studies corroborating the evidence described above is obtained, the variant was conservatively classified as uncertain significance.