Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003313369 | SCV004012144 | pathogenic | Maturity-onset diabetes of the young type 2 | 2023-06-26 | reviewed by expert panel | curation | The c.1256del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 419 (NM_000162.5), adding 12 novel amino acids before encountering a stop codon (p.(Phe419SerfsTer12)). 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 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 25015100, PMID: 29056535, PMID: 33414663 and internal lab contributors). This variant has been detected in at least two individuals with neonatal diabetes. Of those individuals, two were homozygous. (PM3; PMID: 25015100, PMID: 29056535, internal lab contributors). 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%, antibody negative, and 3 generation dominant family history of diabetes) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.1256del 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, PS4_Moderate, PM3, PP4_moderate. |