Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003325962 | SCV004032087 | pathogenic | Monogenic diabetes | 2023-08-12 | reviewed by expert panel | curation | The c.776C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 259 (p.(Ala259Val)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in 15 unrelated individuals with hyperglycemia (PS4; PMID:22035297, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 16 informative meioses in 5 families (PP1_Strong; PMID: 22035297, 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). Another missense variant, c.775G>A, p.Ala259Thr has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala259Val has a greater Grantham distance (PM5). Lastly, this variant was identified in two individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). In summary, c. 776C>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): PP3, PM2_Supporting, PS4, PP1_Strong, PP2, PM5, PP4_Moderate. |
| Athena Diagnostics | RCV000518148 | SCV000613457 | uncertain significance | not specified | 2017-03-03 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics, |
RCV002413397 | SCV002605071 | likely risk allele | Maturity onset diabetes mellitus in young | criteria provided, single submitter | research | Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554335132 in MODY, yet. | |
| Ambry Genetics | RCV002413397 | SCV002672208 | likely pathogenic | Maturity onset diabetes mellitus in young | 2021-03-17 | criteria provided, single submitter | clinical testing | The p.A259V variant (also known as c.776C>T), located in coding exon 7 of the GCK gene, results from a C to T substitution at nucleotide position 776. The alanine at codon 259 is replaced by valine, an amino acid with similar properties. This alteration has been reported in multiple individuals with a clinical and family history consistent with GCK-MODY (Tracz A et al. Exp Clin Endocrinol Diabetes, 2014 Oct;122:503-9; Borowiec M et al. Clin Genet, 2012 Dec;82:587-90). In addition, another alteration at the same codon, p.A259T (c.775G>A), has been described in multiple individuals meeting MODY diagnostic criteria (Capuano M et al. PLoS One, 2012 Jun;7:e38906; Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172); in one report, p.A259T was confirmed de novo in an individual with impaired glucose tolerance diagnosed in childhood, C-peptide secretion/detectable insulin in absence of insulin treatment, who was also negative for autoantibodies (Glotov OS et al. Mol Med Rep, 2019 Dec;20:4905-4914). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cheruvallath ZS et al. Bioorg Med Chem Lett, 2017 06;27:2678-2682). This amino acid position is well 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. |