Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523346 | SCV000621860 | pathogenic | not provided | 2024-04-19 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36257325, 30592380, 34686905, 32533152) |
| Laboratory for Molecular Medicine, |
RCV000826165 | SCV000967703 | likely pathogenic | Maturity onset diabetes mellitus in young | 2018-08-29 | criteria provided, single submitter | clinical testing | The p.Tyr214X variant in GCK has been reported (as p.Tyr215X) in 1 individual wi th clinical features of gestational diabetes (Ellard 2000). This variant has als o been reported in ClinVar (Variation ID# 453007) and is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense v ariant leads to a premature termination codon, which is predicted to lead to a t runcated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in MODY. In summary, although additional studies a re required to fully establish its clinical significance, the p.Tyr214X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2. |
| Labcorp Genetics |
RCV000523346 | SCV002236305 | pathogenic | not provided | 2023-12-27 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr215*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 30592380). ClinVar contains an entry for this variant (Variation ID: 453007). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000826165 | SCV004057901 | pathogenic | Maturity onset diabetes mellitus in young | 2023-08-02 | criteria provided, single submitter | clinical testing | The p.Y215* pathogenic mutation (also known as c.645C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at nucleotide position 645. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in several individuals with maturity-onset diabetes of the young (Thomson KL et al. Hum Mutat, 2003 Nov;22:417; Sagen JV et al. Pediatr Diabetes, 2008 Oct;9:442-9; Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971; Patel KA et al. Diabetologia, 2022 Feb;65:336-342). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |