Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000711787 | SCV000842184 | pathogenic | not provided | 2020-10-14 | criteria provided, single submitter | clinical testing | This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420913 | SCV001623362 | likely pathogenic | Maturity-onset diabetes of the young type 2 | 2024-10-04 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.863+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of GCK function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 241310 control chromosomes. c.863+1G>A has been reported in the literature in heterozygous individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (Alkorta-Aranburu_2014, Harsunen_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25306193, 36418577, 35229243). ClinVar contains an entry for this variant (Variation ID: 585928). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV000711787 | SCV002235594 | pathogenic | not provided | 2024-10-13 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 7 of the GCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 19790256, 21696527, 25306193). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585928). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Geisinger Clinic, |
RCV001420913 | SCV002562196 | pathogenic | Maturity-onset diabetes of the young type 2 | 2022-08-02 | criteria provided, single submitter | research | PVS1, PM2, PS4_Supporting, PS1_Moderate, PP4 |
| Fulgent Genetics, |
RCV005034335 | SCV005668346 | pathogenic | Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1 | 2024-03-08 | criteria provided, single submitter | clinical testing |