ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.118G>A (p.Glu40Lys)

dbSNP: rs794727236
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV005054175 SCV005687807 pathogenic Monogenic diabetes 2025-01-29 reviewed by expert panel curation The c.118G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 40 (p.(Glu40Lys)) of NM_000162.5. 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 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.069, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 25015100). This variant was identified in at least 33 unrelated individuals with hyperglycemia (PS4; PMID: 22332836, 29207974, 25015100, Internal lab contributors). This variant segregated with hyperglycemia, with four informative meioses in three families (PP1_Strong; PMID: 24804978, Internal lab contributors). 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%, antibody negative) (PP4_Moderate; Internal lab contributor). This variant has been detected in the homozygous state in one individual with neonatal diabetes (PM3_Supporting; PMID: 25015100). In summary, c.118G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PS3_Moderate, PP1_Strong, PP2, PP3, PM2_Supporting, PM3_Supporting
Eurofins Ntd Llc (ga) RCV000175536 SCV000227038 pathogenic not provided 2014-11-22 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV003388832 SCV004100719 likely pathogenic Maturity-onset diabetes of the young type 2 2023-10-16 criteria provided, single submitter clinical testing Criteria applied: PS4,PM2_SUP,PP2,PP3

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