Submissions for variant NM_001165963.4(SCN1A):c.1170+5G>C

dbSNP: rs1057524737

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443082	SCV000536348	likely pathogenic	not provided	2017-01-27	criteria provided, single submitter	clinical testing	A novel c.1170+5 G>C variant that is likely pathogenic has been identified in the SCN1A gene. The c.1170+5 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1170+5 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1170+5 G>C may destroy the natural donor site in intron 8 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071465	SCV001236771	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2019-04-03	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the SCN1A gene. It does not directly change the encoded amino acid sequence of the SCN1A protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). A different variant affecting this nucleotide (c.1170+5G>A) has been determined to be pathogenic (Invitae). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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. This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 393000). 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.