Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001248971 | SCV004697917 | pathogenic | Monogenic diabetes | 2024-02-28 | reviewed by expert panel | curation | The c.682A>G variant in the glucokinase gene, GCK, causes an amino acid change of threonine to alanine at codon 228 (p.(Thr228Ala)) 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 0.931 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 has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 1 copy in the East Asian subpopulation and no copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4, PMIDs: 31638168, 12955723, internal lab contributors). Another missense variant, c.683C>T p.Thr228Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr228Ala (PM5_Supporting). In summary, c.682A>G 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, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting, PS4. |
| Athena Diagnostics | RCV000516688 | SCV000613450 | likely pathogenic | not provided | 2017-11-03 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV001248971 | SCV001422803 | likely pathogenic | Monogenic diabetes | 2020-01-22 | criteria provided, single submitter | curation | The p.Thr228Ala variant in GCK has been reported in 3 Italian individuals with Monogenic Diabetes, segregated with disease in these 3 affected relatives from 1 family (PMID: 12955723), and has been identified in 0.005442% (1/18374) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 447413). In vitro functional studies provide some evidence that the p.Thr228Ala variant may impact ATP binding (PMID: 15752705, 15102714, 19790256). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One pathogenic variant with a different amino acid change at the same position, p.Thr228Met, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 16134). Multiple variants in the same region as p.Thr228Ala have been reported in association with disease in ClinVar and the literature, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (PMID: 22389783; Variation ID: 36244, 36243, 546098). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PM5, PM2_Supporting, PP3, PM1_Supporting, PP1 (Richards 2015). |
| Ambry Genetics | RCV002367714 | SCV002664961 | uncertain significance | Maturity onset diabetes mellitus in young | 2017-12-14 | criteria provided, single submitter | clinical testing | The p.T228A variant (also known as c.682A>G), located in coding exon 7 of the GCK gene, results from an A to G substitution at nucleotide position 682. The threonine at codon 228 is replaced by alanine, an amino acid with similar properties. This variant was detected in three individuals with maturity-onset diabetes of the young; all three individuals were considered related in the study, although only two were known to be related at the time of participant recruitment (Mantovani V et al. Hum. Mutat., 2003 Oct;22:338). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000516688 | SCV003440138 | likely pathogenic | not provided | 2022-03-04 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 228 of the GCK protein (p.Thr228Ala). This variant is present in population databases (no rsID available, gnomAD 0.006%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr228 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22335469, 24323243, 31638168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GCK function (PMID: 15752705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 447413). This missense change has been observed in individuals with clinical features of autosomal dominant GCK-related conditions (PMID: 12955723, 31638168; Invitae). |