Submissions for variant NM_001040142.2(SCN2A):c.3964G>A (p.Gly1322Arg)

dbSNP: rs1057521223

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000440836	SCV000521689	likely pathogenic	not provided	2015-12-17	criteria provided, single submitter	clinical testing	The G1322R variant in the SCN2A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G1322R variant 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 G1322R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R1319Q, M1323V, V1326L, V1326D) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G1322R variant is a strong candidate for a pathogenic variant.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000440836	SCV000804353	likely pathogenic	not provided	2018-01-29	criteria provided, single submitter	provider interpretation	This is a 12 year old male with intellectual disability, autism spectrum disorder, mild hyptonia, hyperkinesis, and sleep problems. He has no history of seizures. This variant is absent from the gnomAD database. Computational models predict it to be deleterious, and it was found to be de novo (with maternity and paternity confirmed). Other nearby missense variants have been reported in the Human Gene Mutation Database, but in association to seizures rather than intellectual disability/autism spectrum disorder.