ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.605T>C (p.Met202Thr) (rs193922311)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029896 SCV000052551 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing Variant summary: The variant, GCK c.605T>C (p.Met202Thr) results in a non-conservative amino acid change located in the Hexokinase, N-terminal 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 allele was found at a frequency of 8.1e-06 in 246536 control chromosomes (gnomAD). The variant, c.605T>C has been reported in the literature in individuals affected with Maturity Onset Diabetes of the Young 2 (Chambers_2016, Estalella_2007, Gozalan_2012). In one of these reports, this variant was reported as a de-novo occurrence however the data provided does not confirm this finding (Gozalan_2012; ACMG PM6). Furthermore, one of these reports reflects a conflicting classification of this variant relative to its latest ClinVar submission by the same testing laboratory (Chambers_2016). These data indicate that the variant is likely to be associated with disease. 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 has 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 three new reports indicating its presence in individuals diagnosed with MODY2 or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until additional functional impact and unequivocal co-segregation with disease in additional families/individuals with MODY2 is obtained the variant was classified as VUS Possibly Pathogenic.
Athena Diagnostics Inc RCV000711779 SCV000842175 likely pathogenic not provided 2019-05-09 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One de novo case without parental identity confirmed.

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