Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003493719 | SCV004242353 | likely pathogenic | Monogenic diabetes | 2024-01-28 | reviewed by expert panel | curation | The c.1310C>T variant in the glucokinase gene, GCK, causes an amino acid change of threonine to isoleucine at codon 437 (p.(Thr437Ile)) 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 0.7269, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in 4 unrelated individuals with hyperglycemia; (PS4_Moderate; ClinVar ID 585914, PMID 28323911, internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and documented persistent impaired fasting glucose or negative antibodies) (PP4_Moderate; PMID: 28323911, internal lab contributors). In summary, c.1310C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate. |
| Athena Diagnostics | RCV000711765 | SCV000842159 | uncertain significance | not provided | 2018-06-07 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000764717 | SCV000895851 | uncertain significance | Permanent neonatal diabetes mellitus; Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000711765 | SCV004295122 | uncertain significance | not provided | 2023-04-26 | criteria provided, single submitter | clinical testing | 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 not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 585914). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 28323911). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 437 of the GCK protein (p.Thr437Ile). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |