Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001837265 | SCV002097778 | uncertain significance | Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13 | 2021-04-07 | criteria provided, single submitter | clinical testing | The inherited c.3820-1G>T (p.?) splice acceptor variant in intron 20 of 26 of SCN8A has not been reported in affected individuals in the available literature. The flanking coding exon 20 in NM_001330260.2, encodes the previously described alternatively spliced exon 18A [PMID:9295353]. The c.3820-1G>T variant is predicted to result in an in-frame deletion of coding exon 20/exon 18A [PMID: 30192042] and encode a truncated transmembrane domain III of Nav1.6. This variant is absent in gnomADv3 and v2, suggesting it is not a common benign variant in the populations represented in this database. However, a heterozygous variant at the adjacent splice acceptor site (c.3820-2A>T) was seen in 14 individuals in gnomADv2 population database. It is currently unclear whether the gnomADv2 variants in this region are low quality artefactual calls or true variants. In silico predictions for the c.3820-1G>T variant were consistent with low to moderate effect on splicing [Splice AI score: 0.11 for acceptor loss; TraP score: 0.642]. Further, in affected individuals, LoF variants including canonical splice site changes, have so far not been reported in this alternatively spliced SCN8A exon. Notably, only a handful of canonical splice site variants have been reported in SCN8A constitutive exons in association with disease [PMIDs: 25568300, 29100083, 33007625]. Given the weak in silico predictions, lack of experimental and additional genetic evidence, the inherited SCN8A c.3820-1G>T (p.?) splice acceptor variant is currently classified as a Variant of uncertain significance. |