Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003480801 | SCV004223870 | pathogenic | Monogenic diabetes | 2023-12-15 | reviewed by expert panel | curation | The c.322T>C variant in the glucokinase gene, GCK, causes an amino acid change of tyrosine to histidine at codon 108 (p.(Tyr108His)) 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 0.949, which is [greater than/equal to] the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 14 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 19564454, ClinVar ID: 585918, internal lab contributors), including an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in multiple families (internal lab contributors). In summary, c.322T>C 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): PP1_Strong, PS4, PP2, PP3, PP4, PM2_Supporting. |
| Athena Diagnostics Inc | RCV000711770 | SCV000842166 | likely pathogenic | not provided | 2019-01-23 | criteria provided, single submitter | clinical testing | Not found in the total gnomAD dataset, and the data is high quality (0/282834 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. |
| Gene |
RCV000711770 | SCV004169132 | likely pathogenic | not provided | 2023-10-26 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 9662401, 19790256, 14517956, 17573900, 19564454) |