Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003325941 | SCV004032070 | pathogenic | Monogenic diabetes | 2023-08-07 | reviewed by expert panel | curation | The c.1132G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 378 (p.(Ala378Thr) of NM_000162.5. This variant failed quality control check in gnomAD 2.1.1; however, it is absent in multiple large population cohorts (UKBiobank, BioMe, Geisinger, internal lab contributors) and therefore the ClinGen MDEP has approved the application of PM2_Supporting for this variant (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1133C>T (p.(Ala378Val)), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala378Thr (PM5_Supporting). Additionally, 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 has been identified in over 30 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID 18248649, PMID 16965331, internal lab contributors). This variant segregates with diabetes in 15 informative meioses in a large extended family with diabetes (PP1_Strong; internal lab contributor). This variant was identified in an individual with 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; internal lab contributors). In summary, c.1132G>A 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): PM2_Supporting, PP3, PM5_Supporting, PP2, PS4, PP1_Strong, PP4_moderate. |
| Invitae | RCV002513080 | SCV003440135 | uncertain significance | not provided | 2022-08-26 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16145). This missense change has been observed in individual(s) with GCK-related conditions (PMID: 16965331, 18248649). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 378 of the GCK protein (p.Ala378Thr). |
| OMIM | RCV000017527 | SCV000037799 | pathogenic | Maturity-onset diabetes of the young type 2 | 2006-10-01 | no assertion criteria provided | literature only |