Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003313366 | SCV004012141 | pathogenic | Maturity-onset diabetes of the young type 2 | 2023-06-25 | reviewed by expert panel | curation | The c.1261G>T variant in the glucokinase gene, GCK, results in a premature termination at codon 421 (p.(Glu421Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and fasting glucose between 5.5-8 mmol/L) (PP4; internal lab contributors). In summary, c.1261G>T 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): PVS1, PM2_supporting, PP4. |