Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000649654 | SCV000771483 | uncertain significance | Intellectual disability, autosomal dominant 8 | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 643 of the GRIN1 protein (p.Ile643Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GRIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539837). Advanced 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 at Invitae 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 GRIN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Unidad de Genómica Garrahan, |
RCV002283502 | SCV002573458 | likely pathogenic | Developmental and epileptic encephalopathy, 1 | 2022-12-02 | criteria provided, single submitter | clinical testing | The novel genetic variant identified in case (NM_007327.4:c.1927A>G-p.Ile643Val) affects a highly conserved amino acid in the second segment (S2) of the extracellular LBD involved in binding the co-agonists glutamate and glycine/D-serine. Specifically, the Ile643 position is located in the loop that connects the LBD with the TMD, a loop that is also involved in the interaction between subunits of the NMDA. In turn, in a previous study in which pathogenic and non-pathogenic variants were mapped to the structure of NMDA, it was shown that this loop is extremely critical and that all the variants reported in this region affect protein function. Therefore, the structural prediction would be pathogenic; however, since we do not have functional studies that demonstrate the gain or loss of function, the variant was classified as likely pathogenic according to the ACMG guidelines (PM1, PM2, PP2, PP3). |