Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000706633 | SCV000835696 | pathogenic | Landau-Kleffner syndrome | 2022-11-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GRIN2A protein in which other variant(s) (p.Trp1271*) have been determined to be pathogenic (PMID: 29961510). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 582537). This variant has not been reported in the literature in individuals affected with GRIN2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1014*) in the GRIN2A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 451 amino acid(s) of the GRIN2A protein. |
| Broad Center for Mendelian Genomics, |
RCV000706633 | SCV003761365 | likely pathogenic | Landau-Kleffner syndrome | 2023-01-25 | criteria provided, single submitter | curation | The heterozygous p.Trp1014Ter variant in GRIN2A was identified by our study in one individual with epilepsy and developmental delay. This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. The p.Trp1014Ter variant in GRIN2A has not been previously reported in individuals with focal epilepsy with speech disorder. This variant has also been reported in ClinVar (Variation ID: 582537) and has been interpreted as a variant of uncertain significance by Invitae. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1014. This alteration occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the GRIN2A gene is an established disease mechanism in autosomal dominant focal epilepsy with speech disorder. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for focal epilepsy with speech disorder. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM6_Supporting (Richards 2015). |