Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000439430 | SCV000534991 | uncertain significance | not provided | 2017-01-05 | criteria provided, single submitter | clinical testing | The K339R variant in the TTC7A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K339R variant was not observed in approximately 6500 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 K339R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across mammalian species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.1016 A>G (aka K339R) might create a cryptic splice acceptor site for intron 7 which may supplant the natural acceptor site. However, in the absence of RNA/functional studies, the actual effect of c.1016 A>G in this individual is unknown. We interpret K339R as a variant of uncertain significance. |
| Labcorp Genetics |
RCV000793018 | SCV000932352 | uncertain significance | Multiple gastrointestinal atresias | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 339 of the TTC7A protein (p.Lys339Arg). This variant is present in population databases (rs777088531, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with TTC7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 391836). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TTC7A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |