Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004527570 | SCV005040677 | pathogenic | Monogenic diabetes | 2024-04-27 | reviewed by expert panel | curation | The c.1234G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 412 (p.(Val412Met)) 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 0.82, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 2 hour OGTT glucose increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). Three other missense variants, c.1235T>A p.Val412Glu, c.1235T>C Val412Ala, and c.1235T>G Val412Gly have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.1234G>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: PM5_Strong, PP4_Moderate, PM1, PP2, PP3, PM2_Supporting. |
| Fulgent Genetics, |
RCV005038707 | SCV005668331 | likely pathogenic | Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1 | 2024-05-25 | criteria provided, single submitter | clinical testing |