ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.824G>T (p.Arg275Leu)

dbSNP: rs767565869
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003330317 SCV004037460 likely pathogenic Monogenic diabetes 2025-01-10 reviewed by expert panel curation The c.824G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 275 (p.(Arg275Leu)) of NM_000162.5. This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.702, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants at this residue, c.823C>T p.(Arg275Cys) and c.823C>G (p.Arg275Gly), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.824G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting.
Genetic Services Laboratory, University of Chicago RCV000504015 SCV000594963 likely pathogenic Maturity-onset diabetes of the young type 2 2017-05-18 criteria provided, single submitter clinical testing

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