Submissions for variant NM_001165963.4(SCN1A):c.4321G>A (p.Ala1441Thr)

dbSNP: rs121917974

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413422	SCV000491509	likely pathogenic	not provided	2016-06-22	criteria provided, single submitter	clinical testing	The A1441T variant in the SCN1A gene has been reported previously in a patient with Dravetsyndrome (Lee et al., 2015). The A1441T variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The A1441T variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aconserved position within the pore forming loop between the S5 and S6 transmembrane segments ofthe third homologous domain. In silico analysis predicts this variant is probably damaging to theprotein structure/function. The A1441T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rarebenign variant cannot be excluded.
Invitae	RCV000692374	SCV000820194	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-03-23	criteria provided, single submitter	clinical testing	This variant disrupts the p.Ala1441 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31765958). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 372966). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 25459968, 31618753). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1441 of the SCN1A protein (p.Ala1441Thr). For these reasons, this variant has been classified as Pathogenic.