Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003480800 | SCV004223875 | pathogenic | Monogenic diabetes | 2024-07-25 | reviewed by expert panel | curation | The c.185T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 62 (p.(Val62Ala)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.97, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.23, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 16731834). This variant has an incomputable Popmax filtering allele frequency in gnomAD v2.1.1 due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African subpopulation, below the ClinGen MDEP threshold for PM2_Supporting (Popmax FAF ≤0.000003 and ≤ 2 copies in ENF and ≤1 copy in any other subpopulation) (PM2_Supporting). It was identified in at least two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18399931, PMID: 9736233, ClinVar ID: 585917). One of these individuals has 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; PMID: 18399931). This variant segregated with diabetes, with five informative meioses in one family with MODY (PP1_Strong; PMID: 9736233, internal lab contributors). Another missense variant, c.184G>A (p.Val62Met) has been interpreted as pathogenic by the ClinGen MDEP and p.Val62Ala has a greater Grantham distance (PM5). In summary, the c.185T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP1_Strong, PM5, PS3_Moderate, PP2, PP3, PM2_Supporting. |
| Athena Diagnostics | RCV000711769 | SCV000842163 | likely pathogenic | not provided | 2018-04-05 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000711769 | SCV002241876 | pathogenic | not provided | 2024-09-04 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 62 of the GCK protein (p.Val62Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 9736233, 23306198). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585917). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 16731834, 23306198). This variant disrupts the p.Val62 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15677479, 17389332, 19187021, 21831042). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |