Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001420575 | SCV001622890 | likely pathogenic | Landau-Kleffner syndrome | 2020-05-06 | criteria provided, single submitter | clinical testing | The inherited c.1778-2A>C variant identified in the GRIN2A gene is a canonical splice variant within intron 8/12 (NM_001134407.3), and is a canonical splice acceptor at exon 9/13. The thymine nucleotide at this position is fully conserved. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. Human Splicing Finger predicts this variant leads to the alteration of the wildtype splice acceptor site and most probably affects splicing, and the Transcript inferred Pathogenicity (TraP; v3.0) score for this variant is 0.582, which is >99% score-percentile for non-coding variants, suggesting it is probably damaging. This variant is absent from ClinVar and to our current knowledge has not been reported in the literature, however other canonical splice variants have been reported as Likely Pathogenic/Pathogenic in ClinVar, as well as in affected individuals in the literature [PMID:28109652; PMID:27683935]. The canonical splice variant identified in this individual is proximal to amino acid residue p.Ala593, which is just upstream of the pore-forming domain of GRIN2A (UniProtKB:Q12879), and many individuals have been reported in the literature with variants within and around this region [PMID:23933820]. Given its deleterious nature, predicted effect on splicing, and absence in population databases, the inherited c.1778-2A>C variant identified in the GRIN2A gene is reported here as Likely Pathogenic. |