Submissions for variant NM_001165963.4(SCN1A):c.301C>T (p.Arg101Trp)

dbSNP: rs121917965

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Bioinformatics, Peking University	RCV000059399	SCV000221765	pathogenic	Severe myoclonic epilepsy in infancy	2014-12-20	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000357692	SCV000344955	pathogenic	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541714	SCV000633843	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the SCN1A protein (p.Arg101Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe myoclonic epilepsyof infancy (SMEI) and Dravet Syndrome (PMID: 17347258, 20431604, 24168886, 27113213, 27236449). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68527). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg101 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20431604, 23195492, 23808377, 24328833, 25885068). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000357692	SCV001249712	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199316	SCV001370396	pathogenic	Migraine, familial hemiplegic, 3	2019-05-06	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3,PM2,PM1.
Lifecell International Pvt. Ltd	RCV000059399	SCV001738772	likely pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.301C>T) in exon 5 of the SCN1A gene that results in the amino acid substitution from Arginine to Tryptophan at codon 101 (p.Arg101Trp) was identified. There is a moderate physicochemical difference between Arginine and Tryptophan. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). This variant has previously been reported for Dravet syndrome by Usluer S et al., 2016. This variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 68527 as of 2020-06-04). Based on the above evidence this variant has been classified as Likely pathogenic according to the ACMG guidelines.
GeneDx	RCV000357692	SCV002499971	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	This substitution is predicted to be within the N-terminal cytoplasmic domain; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19585586, 20431604, 26096185, 27113213, 27236449, 29933521, 17347258, 18930999, 29852413, 30619928, 31164858, 31864146, 32090326, 29573403, 33278787, 31031587)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000059399	SCV004812080	pathogenic	Severe myoclonic epilepsy in infancy	2024-08-30	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PS2_MOD,PS4_MOD,PM2_SUP,PP2,PP3
UniProtKB/Swiss-Prot	RCV000059399	SCV000090923	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided