Submissions for variant NM_001040142.2(SCN2A):c.647T>G (p.Leu216Trp)

dbSNP: rs796053203

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189243	SCV000242875	likely pathogenic	not provided	2012-02-23	criteria provided, single submitter	clinical testing	The Leu216Trp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Leu216Trp in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although both Leucine and Tryptophan are non-polar, Tryptophan is a larger residue with an aromatic side chain. The Leu216Trp substitution alters a highly conserved position in the S4 segment of the first transmembrane domain of the protein, and a different mutation in this same segment has been published in association with benign familial neonatal-infantile seizures (BFNIS) (Berkovic et al., 2004). Additionally, multiple in silico algorithms predict that Leu216Trp is damaging to protein structure/function. Therefore, Leu216Trp is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded at present. The variant is found in INFANT-EPI panel(s).
Invitae	RCV001390241	SCV001591910	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2022-02-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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"). ClinVar contains an entry for this variant (Variation ID: 207088). This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 30109124; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 216 of the SCN2A protein (p.Leu216Trp).