Description
A apparently de novo c.1662 G>C pathogenic variant has been identified in the SCN1A gene. The c.1662 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different nucleotide substitution (c.1662 G>T) resulting in the same amino acid change (Q554H) has been reported previously as a de novo variant in an individual with Dravet syndrome (Gaily et al., 2013). Additionally, a different missense change at the same position (Q554R) has also been reported as a de novo variant in an individual with Dravet syndrome (Skjei et al., 2015). The c.1662 G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.1662 G>C damages or destroys the natural donor site for intron 10 and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.1662 G>C variant does not affect splicing, it will result in a Q554H missense variant. The Q554H 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 conserved position predicted to be in the cytoplasmic loop between the first and second homologous domains. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we now interpret c.1662 G>C as a pathogenic variant.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
