ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.757G>A (p.Val253Ile) (rs748964205)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482178 SCV000565030 likely pathogenic not provided 2014-11-19 criteria provided, single submitter clinical testing A novel V253I variant that is likely pathogenic was identified in the GCK gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The V253I variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The V253I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Another conservative missense variant in the same residue (V253A), as well as missense variants in nearby residues (M251I, C252R/G/Y, N254H, T255A/S) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.

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