Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003318501 | SCV004022349 | pathogenic | Monogenic diabetes | 2023-07-16 | reviewed by expert panel | curation | The c.1144T>C variant in the glucokinase gene, GCK, causes an amino acid change of Cys to Arg at codon 382 (p.(Cys382Arg)) of NM_000162.5. 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 0.967 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1144T>G p.Cys382Gly, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:24804978, Zubkova N.A et al, World J PM. 2017;1(1):40-48. https://doi.org/10.14341/WJPM9298, internal lab contributors). In summary, c.1144T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5_Supporting, PP4_Moderate, PS4. |
| Athena Diagnostics | RCV000517422 | SCV000613402 | uncertain significance | not specified | 2017-05-26 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics, |
RCV002463695 | SCV002605091 | likely pathogenic | Maturity onset diabetes mellitus in young | criteria provided, single submitter | research | Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554334613 in MODY, yet. | |
| Labcorp Genetics |
RCV002525034 | SCV003439927 | pathogenic | not provided | 2023-04-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 447384). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 19790256, 24804978; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 382 of the GCK protein (p.Cys382Arg). |