Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189172 | SCV000242804 | uncertain significance | not provided | 2013-07-01 | criteria provided, single submitter | clinical testing | p.Arg1632Lys (AGG>AAG): c.4895 G>A in exon 27 in the SCN2A gene (NM_021007.2). The R1632K mutation in the SCNA2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The R1632K mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1632K mutation is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution alters a highly conserved position in the voltage sensor S4 segment of the fourth transmembrane domain of the SCN2A protein. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Recently, two nearby missense mutations (T1623N and R1629L) were reported in association with early-onset epileptic encephalopathy (Nakamura et al. 2013). Parental testing was not available for the R1629L mutation but the T1623N mutation was found to be de novo (Nakamura et al. 2013). This data supports the functional importance of this region of the protein. Additionally, recent publications have reported missense mutations in neighboring codons supporting the functional importance of this region of the protein. Therefore, we interpret R1632K as a disease-causing mutation. The variant is found in INFANT-EPI panel(s). |