Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002387880 | SCV002690290 | uncertain significance | Maturity onset diabetes mellitus in young | 2017-12-20 | criteria provided, single submitter | clinical testing | The p.A450S variant (also known as c.1348G>T), located in coding exon 10 of the GCK gene, results from a G to T substitution at nucleotide position 1348. The alanine at codon 450 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003774278 | SCV004642448 | pathogenic | not provided | 2024-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 450 of the GCK protein (p.Ala450Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant GCK-related conditions (PMID: 32370465, 35472491; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1770532). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. This variant disrupts the p.Ala450 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 31638168; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | RCV003774278 | SCV005620660 | likely pathogenic | not provided | 2024-02-20 | criteria provided, single submitter | clinical testing | This variant has been identified in at least one individual with clinical features associated with MODY. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203) |