Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000665071 | SCV000789130 | uncertain significance | Tyrosinemia type II | 2017-01-13 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000665071 | SCV000962726 | likely pathogenic | Tyrosinemia type II | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 433 of the TAT protein (p.Arg433Gln). This variant is present in population databases (rs775488556, gnomAD 0.006%). This missense change has been observed in individual(s) with tyrosinemia type II (PMID: 9544843). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 550347). 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 TAT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TAT function (PMID: 9544843). This variant disrupts the p.Arg433 amino acid residue in TAT. Other variant(s) that disrupt this residue have been observed in individuals with TAT-related conditions (PMID: 9544843), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000665071 | SCV002547986 | likely pathogenic | Tyrosinemia type II | 2022-05-13 | criteria provided, single submitter | clinical testing | Variant summary: TAT c.1298G>A (p.Arg433Gln) results in a conservative amino acid change located in the Aminotransferase, class I/class II domain (IPR004839) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251422 control chromosomes. c.1298G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Tyrosinemia Type 2 who continue to be cited in subsequent reports (example, Huhn_1998, Pena-Quintana_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Huhn_1998). The most pronounced variant effect results in a drastically reduced TAT enzyme activity in-vitro when compared with the GST-TAT wild type construct. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000665071 | SCV004205708 | likely pathogenic | Tyrosinemia type II | 2023-10-05 | criteria provided, single submitter | clinical testing |