Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003318514 | SCV004022338 | likely pathogenic | Monogenic diabetes | 2025-04-22 | reviewed by expert panel | curation | The c.1181G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 394 (p.(Arg394Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.851, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L)(PP4_Moderate; internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). Additionally, it segregated with diabetes with 2 informative meioses in 2 families (PP1; internal lab contributors). In summary, c.1181G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PP1, PP2, PP3, PP4_Moderate, PM2_Supporting, PS4_Moderate. |
| Labcorp Genetics |
RCV003084866 | SCV003483366 | uncertain significance | not provided | 2024-06-10 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 394 of the GCK protein (p.Arg394Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 31063852). ClinVar contains an entry for this variant (Variation ID: 2169517). 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 with a negative predictive value of 80%. 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. |
| Athena Diagnostics | RCV003084866 | SCV005621368 | uncertain significance | not provided | 2023-11-07 | criteria provided, single submitter | clinical testing | Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is damaging. |