Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000419698 | SCV000520937 | likely pathogenic | not provided | 2016-09-20 | criteria provided, single submitter | clinical testing | The I262N variant in the FAS gene has not been published in association with autoimmune lymphoproliferative syndrome (ALPS) to our knowledge. The 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. I262N 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 occurs at a position within the critical death domain that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (I262S/T) and in nearby residues (A257D, I259T/R, D260H/Y/N/V/G) have been reported in the Human Gene Mutation Database in association with FAS-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |