ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.682A>G (p.Thr228Ala) (rs1332966015)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516688 SCV000613450 likely pathogenic not provided 2017-11-03 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001248971 SCV001422803 likely pathogenic Monogenic diabetes 2020-01-22 no assertion criteria provided curation The p.Thr228Ala variant in GCK has been reported in 3 Italian individuals with Monogenic Diabetes, segregated with disease in these 3 affected relatives from 1 family (PMID: 12955723), and has been identified in 0.005442% (1/18374) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. 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: 447413). In vitro functional studies provide some evidence that the p.Thr228Ala variant may impact ATP binding (PMID: 15752705, 15102714, 19790256). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One pathogenic variant with a different amino acid change at the same position, p.Thr228Met, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 16134). Multiple variants in the same region as p.Thr228Ala have been reported in association with disease in ClinVar and the literature, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (PMID: 22389783; Variation ID: 36244, 36243, 546098). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PM5, PM2_Supporting, PP3, PM1_Supporting, PP1 (Richards 2015).

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