Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000486330 | SCV000571051 | likely pathogenic | not provided | 2016-08-12 | criteria provided, single submitter | clinical testing | The L175P variant in the TYR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L175P 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 variant in these populations. The L175P 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 where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (F176I, V177F, V177D, M179L, H180N, H180R) have been reported in the Human Gene Mutation Database in association with oculocutaneous albinism type 1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L175P as a likely pathogenic variant. |
| Labcorp Genetics |
RCV000486330 | SCV003226170 | uncertain significance | not provided | 2021-12-27 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 175 of the TYR protein (p.Leu175Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TYR-related conditions. ClinVar contains an entry for this variant (Variation ID: 421753). 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 expected to disrupt TYR protein function. 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. |