Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255765 | SCV000322027 | likely pathogenic | not provided | 2016-06-23 | criteria provided, single submitter | clinical testing | The Y1769C variant that is likely pathogenic has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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. The Y1769C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution alters a conserved position predicted to be within the transmembrane segment S6 of the fourth homologous domain of the SCN1A protein. A different missense variant at the same position (Y1769H) as well as missense variants in nearby residues (F1765L, I1771F/N, S1773F) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Ambry Genetics | RCV000624688 | SCV000742333 | likely pathogenic | Inborn genetic diseases | 2017-08-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000624688 | SCV000851607 | likely pathogenic | Inborn genetic diseases | 2017-08-16 | criteria provided, single submitter | clinical testing | The p.Y1769C variant (also known as c.5306A>G), located in coding exon 26 of the SCN1A gene, results from an A to G substitution at nucleotide position 5306. The tyrosine at codon 1769 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been determined to be the result of a de novo mutation in one individual with refractory epilepsy in our laboratory. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |