Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003493616 | SCV004242366 | pathogenic | Monogenic diabetes | 2024-01-18 | reviewed by expert panel | curation | The c.623C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 208 (p.(Ala208Val)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with 9 informative meioses in 6 families (PP1_Strong; internal lab contributors). This variant was identified in 16 unrelated individuals with hyperglycemia (PS4; 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% and a 5 generation family history of diabetes) (PP4_Moderate; internal lab contributors). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as 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 has an incomputable gnomAD v2.1.1 Popmax minor filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). In summary, c.623C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. |
Athena Diagnostics Inc | RCV000517275 | SCV000613445 | uncertain significance | not provided | 2019-08-08 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000517275 | SCV002069648 | likely pathogenic | not provided | 2020-11-30 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002367713 | SCV002659450 | likely pathogenic | Maturity onset diabetes mellitus in young | 2016-04-15 | criteria provided, single submitter | clinical testing | The p.A208V variant (also known as c.623C>T), located in coding exon 6 of the GCK gene, results from a C to T substitution at nucleotide position 623. The alanine at codon 208 is replaced by valine, an amino acid with similar properties. This variant has been reported in a MODY patient (Steele AM, JAMA 2014 Jan; 311(3):279-86). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |