Submissions for variant NM_001165963.4(SCN1A):c.264+5G>A

dbSNP: rs794726762

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000201121	SCV000255818	pathogenic	Severe myoclonic epilepsy in infancy	2015-01-21	criteria provided, single submitter	clinical testing
Invitae	RCV000692637	SCV000820470	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-11-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt 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. ClinVar contains an entry for this variant (Variation ID: 217242). This variant has been observed in individual(s) with severe myoclonic epilepsy of infancy (PMID: 17054684, 25669891). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the SCN1A gene. It does not directly change the encoded amino acid sequence of the SCN1A protein. It affects a nucleotide within the consensus splice site.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197105	SCV001367741	likely pathogenic	Migraine, familial hemiplegic, 3	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000201121	SCV001428706	pathogenic	Severe myoclonic epilepsy in infancy	2019-10-16	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000201121	SCV002578986	likely pathogenic	Severe myoclonic epilepsy in infancy	2022-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469061	SCV002766148	likely pathogenic	Autosomal dominant epilepsy	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.264+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251020 control chromosomes (gnomAD). c.264+5G>A has been reported in the literature in individuals affected with SCN1A-Related Disorders with at-least one reported as a De novo occurrence (example: Berio_2014 and Mancardi_2006). These data indicate that the variant may be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.