Submissions for variant NM_001040142.2(SCN2A):c.562C>T (p.Arg188Trp)

gnomAD frequency: 0.00002  dbSNP: rs121917748

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048768	SCV001212788	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2022-09-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 12875). This missense change has been observed in individual(s) with febrile seizures associated with afebrile seizures (PMID: 11371648, 15301839). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 188 of the SCN2A protein (p.Arg188Trp). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SCN2A function (PMID: 11371648).
GeneDx	RCV002284354	SCV002574368	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing	Identified in an individual with epilepsy who inherited the variant from his father with febrile seizures in the published literature (Sugawara T et al., 2001; Ito et al., 2004), however, molecular analysis was limited to only sequencing of SCN2A; Functional studies demonstrate prolonged open state of the R187W mutant channel which may result in neuronal hyperexcitability (Sugawara T et al., 2001), however additional studies are needed to validate the functional effect of this variant in vivo; Also known as c.562C>T p.(Arg187Trp); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the first homologous domain; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24077912, 28191889, 15048894, 11371648, 15301839, 33004838)
Ambry Genetics	RCV002513021	SCV003561355	uncertain significance	Inborn genetic diseases	2021-08-03	criteria provided, single submitter	clinical testing	The c.562C>T (p.R188W) alteration is located in exon 5 (coding exon 4) of the SCN2A gene. This alteration results from a C to T substitution at nucleotide position 562, causing the arginine (R) at amino acid position 188 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM	RCV000013735	SCV000033982	pathogenic	Seizures, benign familial infantile, 3	2004-04-01	no assertion criteria provided	literature only
Channelopathy-Associated Epilepsy Research Center	RCV002319419	SCV002605522	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only