Submissions for variant NM_001165963.4(SCN1A):c.5734C>T (p.Arg1912Ter)

dbSNP: rs77216276

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586829	SCV000697773	pathogenic	Autosomal dominant epilepsy	2016-02-03	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.5734C>T variant results in a premature termination codon, predicted to cause a truncated or absent SCN1A protein, which is a commonly known mechanism for SCN1A-related seizure disorders. Mutation Taster predicts a damaging outcome for this variant, but functional studies have not been carried out to confirm this prediction. This variant is found in 1/121470 control chromosomes at a frequency of 0.0000082, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0000179). However, the variant has been identified in multiple affected patients in the literature as a de novo mutation, and also as a paternally inherited variant from an asymptomatic mosaic father. Taken together, this is a disease variant and was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001090356	SCV001245857	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV001223212	SCV001395351	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-09-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496124). This variant is also known as R1902X. This premature translational stop signal has been observed in individual(s) with Dravet syndrome (PMID: 14738421, 20522430, 23195492; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs77216276, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1912*) in the SCN1A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the SCN1A protein.
DASA	RCV002221562	SCV002499426	pathogenic	Migraine, familial hemiplegic, 3	2022-04-10	criteria provided, single submitter	clinical testing	The c.5734C>T;p.(Arg1912*) variant creates a premature translational stop signal in the SCN1A gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD) type change; it is present in a relevant exon to the transcript, and disrupts >10% of the protein product. PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 496124 ; PMID: 14738421; 20522430; 21844054; 30868114) - PS4. The variant is present at low allele frequencies population databases (rs77216276 – gnomAD 0.0006579%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 21844054; 30868114) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
GeneDx	RCV001090356	SCV002504091	pathogenic	not provided	2021-11-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 98 amino acids are lost, and other loss-of-function variants have been reported downstream in the published literature; Lost residues are located within the C-terminal cytoplasmic domain and IQ domain; This variant is associated with the following publications: (PMID: 23195492, 21844054, 22344438, 14738421, 31009440, 30868114, 31864146, 32090326, 32540801, 31035242, 20522430)