ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1240A>G (p.Lys414Glu) (rs193922272)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029851 SCV000052506 likely pathogenic Maturity-onset diabetes of the young, type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Athena Diagnostics Inc RCV000711759 SCV000842153 likely pathogenic not provided 2019-05-31 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/253040 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism.
Broad Institute Rare Disease Group,Broad Institute RCV001248969 SCV001422801 likely pathogenic Monogenic diabetes 2020-01-22 no assertion criteria provided curation The p.Lys414Glu variant in GCK has been reported in at least one individual with Monogenic Diabetes (PMID: 8433729), and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36188). In vitro functional studies provide some evidence that the p.Lys414Glu variant may impact protein binding and activity (PMID: 21831042, 8325892, 10525657). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes Monogenic Diabetes (PMID: 17353190). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015).

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