Submissions for variant NM_001349253.2(SCN11A):c.1187T>C (p.Leu396Pro)

dbSNP: rs1085307142

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000489242	SCV000575932	pathogenic	Hereditary sensory and autonomic neuropathy type 7	2017-04-25	criteria provided, single submitter	clinical testing	The following ACMG criteria are met: PS2 (De novo, mat/pat confirmed), PS3 (Functional evidence of gain of function impact), PM2 (Absent from population databases), PP3 (Multiple lines of computational evidence support pathogenicity), PP4 (Highly specific phenotype). A gain of function effect leading to slowed deactivation kinetics and increased channel availability was demontrated in Nav1.9 knock-out murine dorsal root ganglion neurons (PMID:28289907).
GeneDx	RCV000488990	SCV000576869	pathogenic	not provided	2017-04-17	criteria provided, single submitter	clinical testing	The L396P variant in the SCN11A gene has now been published as a disease-related variant associated with SCN11A-related disorders (King et al., 2017). To our knowledge, this individual represents the only reported individual to harbor this variant. The L396P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L396P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies in murine SCN11A knockout dorsal root ganglion neurons transfected with L396P resulted in a slow down of channel deactivation and increase of the resting membrane potential (King et al., 2017). Therefore, we interpret L396P as a pathogenic variant.