Submissions for variant NM_001165963.4(SCN1A):c.301C>T (p.Arg101Trp) (rs121917965)

Total submissions: 7

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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000357692	SCV000344955	pathogenic	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000541714	SCV000633843	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2020-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 101 of the SCN1A protein (p.Arg101Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in several individuals affected with severe myoclonic epilepsy of infancy (SMEI) and Dravet Syndrome (PMID: 17347258, 27236449, 20431604, 24168886, 27113213). ClinVar contains an entry for this variant (Variation ID: 68527). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg101 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23195492, 24328833, 20431604, 25885068, 23808377), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000357692	SCV001249712	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001199316	SCV001370396	pathogenic	Familial hemiplegic migraine type 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.
UniProtKB/Swiss-Prot	RCV000059399	SCV000090923	not provided	Severe myoclonic epilepsy in infancy		no assertion provided	not provided