Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001390786 | SCV001592629 | pathogenic | Intellectual disability, autosomal dominant 8 | 2022-11-03 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Met641 amino acid residue in GRIN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25864721, 27164704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1076783). This missense change has been observed in individual(s) with early onset epilepsy, visual impairment, and developmental delay (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 641 of the GRIN1 protein (p.Met641Val). For these reasons, this variant has been classified as Pathogenic. |
| 3billion | RCV001390786 | SCV003842050 | likely pathogenic | Intellectual disability, autosomal dominant 8 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GRIN1 -related disorder (ClinVar ID: VCV001076783). Different missense changes at the same codon (p.Met641Ile, p.Met641Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000403957, VCV000828036). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |