Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000623855 | SCV000742472 | likely pathogenic | Inborn genetic diseases | 2020-02-19 | criteria provided, single submitter | clinical testing | The alteration results in an amino acid change: The c.5274T>A (p.S1758R) alteration is located in exon 27 (coding exon 26) of the SCN2A gene. This alteration results from a T to A substitution at nucleotide position 5274, causing the serine (S) at amino acid position 1758 to be replaced by an arginine (R). The alteration is not observed in population databases: Based on data from the Genome Aggregation Database (gnomAD), the SCN2A c.5274T>A alteration was not observed, with coverage at this position. The amino acid alteration has been observed in affected individuals: This amino acid substitution, resulting from a different nucleotide change (c.5274T>G), was reported de novo in an individual with autism spectrum disorder, intellectual disability, motor and speech delays, gastrointestinal disturbances, hypotonia, and a history of feeding problems (Guo, 2018). The altered amino acid is conserved throughout evolution: The p.S1758 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain: The p.S1758 amino acid is located in the S6 transmembrane segment of domain IV of Nav1.2 neuronal voltage gated sodium channel. The S5 and S6 segments from each of the four domains form the inner portion of the ion channel pore; the four S6 segments form the wider intracellular end of the pore (Yu, 2003). The alteration is predicted deleterious by in silico modeling: The p.S1758R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |