Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000516357 | SCV000613435 | likely pathogenic | not provided | 2018-03-26 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000516357 | SCV002239174 | pathogenic | not provided | 2024-09-15 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 160 of the GCK protein (p.Asp160Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 19790256, 25015100, 32533152, 33852230, 36257325; internal data). ClinVar contains an entry for this variant (Variation ID: 447404). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 25015100). This variant disrupts the p.Asp160 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29056535, 30608898). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Geisinger Clinic, |
RCV002285349 | SCV002562174 | pathogenic | Maturity-onset diabetes of the young type 2 | 2022-08-02 | criteria provided, single submitter | research | PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3 |
| Clinical Genomics, |
RCV002464023 | SCV002605241 | uncertain 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 rs1554335566 in MODY, yet. | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004701588 | SCV005202974 | uncertain significance | not specified | 2024-07-22 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.478G>A (p.Asp160Asn) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). c.478G>A has been reported in the literature in individuals affected with maturity-onset diabetes of the young as well as in two carriers in non-diabetes (Osbak_2009, Raimondo_2014, Caswell_2020, Breidbart_2021, Mirshahi_2022, Billings_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Raimondo_2014). The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 33852230, 32533152, 36257325, 19790256, 25015100). ClinVar contains an entry for this variant (Variation ID: 447404). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |