Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000493323 | SCV000582197 | likely pathogenic | not provided | 2018-02-02 | criteria provided, single submitter | clinical testing | The L706P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L706P 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. The 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 position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (L706M) and nearby residues (Y705N/C, T708S/N, I711M) have been reported in the Human Gene Mutation Database in association with Hyper-IgE syndrome (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. |
| Labcorp Genetics |
RCV000695153 | SCV000823635 | pathogenic | Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function | 2019-02-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Leu706Pro and p.Leu706Met) in affected individuals suggests that this may be a clinically significant residue (PMID: 20048285, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual with symptoms consistent with hyper IgE syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 429592). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 706 of the STAT3 protein (p.Leu706Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. |