Description
The c.1087G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 363 (p.(Asp363Asn)) of NM_000162.5. This variant was identified in at least 1 individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:19790256, 36257325, internal lab contributor). The individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and three-generation, dominant family history of diabetes (in a family not used for PP1)) (PP4_Moderate; internal lab contributor).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.869, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1088A>G (p.Asp363Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1087G>A 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, PM2_Suporting, PP2, PP3, PM5_Supporting.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |