Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001266945 | SCV001445126 | likely pathogenic | Inborn genetic diseases | 2019-03-12 | criteria provided, single submitter | clinical testing | The alteration results in an amino acid change: The c.136A>G (p.K46E) alteration is located in exon 3 (coding exon 3) of the STXBP1 gene. This alteration results from a A to G substitution at nucleotide position 136, causing the lysine (K) at amino acid position 46 to be replaced by a glutamic acid (E). The alteration is not observed in population databases: Based on data from the Genome Aggregation Database (gnomAD), the STXBP1 c.136A>G alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution: The p.K46 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain: The p.K46 amino acid is on the surface of the SEC1 domain which binds to syntaxin, a component of the synaptic vesicle fusion machinery, and is essential for neurotransmission. Structural analysis performed at Ambry Genetics indicated that the p.K46E alteration is more disruptive than known pathogenic variants (Colbert, 2013). The alteration is predicted deleterious by in silico models: The p.K46E alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic. |