Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003325971 | SCV004032092 | pathogenic | Monogenic diabetes | 2023-08-08 | reviewed by expert panel | curation | The c.1129C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 377 (p.(Arg377Cys)) 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 0.992, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 7 unrelated individuals with hyperglycemia (PS4; PMID 16731834, 20337973, internal lab contributors). 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%) (PP4; PMID: 20337973). This variant segregated with hyperglycemia with two informative meioses in a single family with diabetes, however, this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918, internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg377Cys has RAI=0.01, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate, PMID: 16731834). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PS4, PS3_Moderate, PP4. |
Athena Diagnostics Inc | RCV000711757 | SCV000842151 | uncertain significance | not provided | 2017-08-31 | criteria provided, single submitter | clinical testing |