Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000479259 | SCV000569712 | likely pathogenic | not provided | 2017-06-01 | criteria provided, single submitter | clinical testing | A c.2595+5 G>C variant that is likely pathogenic has been identified in the GRIN2A gene. The c.2595+5 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a nucleotide position that is conserved across species, and multiple in-silico splice prediction models predict c.2595+5 G>C destroys the natural splice donor site of intron 13, leading to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
Invitae | RCV001226009 | SCV001398305 | uncertain significance | Landau-Kleffner syndrome | 2019-08-11 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 13 of the GRIN2A gene. It does not directly change the encoded amino acid sequence of the GRIN2A protein, but it affects a nucleotide within the consensus splice site of the intron. This variant has not been reported in the literature in individuals with GRIN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 420750). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. |