Submissions for variant NM_001165963.4(SCN1A):c.5510C>T (p.Pro1837Leu)

gnomAD frequency: 0.00003  dbSNP: rs149225252

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189006	SCV000242637	uncertain significance	not provided	2021-09-13	criteria provided, single submitter	clinical testing	Previously identified in an individual with seizures (Xiong et al., 2019); This substitution is predicted to be within the C-terminal cytoplasmic domain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31031587)
Invitae	RCV001317294	SCV001507950	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1837 of the SCN1A protein (p.Pro1837Leu). This variant is present in population databases (rs149225252, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of autosomal dominant SCN1A-related conditions (PMID: 31031587; Invitae). ClinVar contains an entry for this variant (Variation ID: 206868). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Centogene AG - the Rare Disease Company	RCV001808472	SCV002059369	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2	2019-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401030	SCV004122121	uncertain significance	not specified	2023-10-25	criteria provided, single submitter	clinical testing	Variant summary: SCN1A c.5510C>T (p.Pro1837Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250318 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5510C>T has been reported in the literature in the heterozygous state in an individual affected with epilepsy who was diagnosed with Dravet syndrome (Xiong_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31031587). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as uncertain significance and one submitter, citing at least one internal observation of the variant in an affected individual, classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.