Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317748 | SCV004020625 | likely pathogenic | Thyroid hormone resistance, generalized, autosomal dominant | 2023-06-09 | criteria provided, single submitter | clinical testing | Variant summary: THRB c.1358C>T (p.Pro453Leu) results in a non-conservative amino acid change located in the ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.1358C>T has been reported in the literature in three individuals (two siblings and their father) affected with Thyroid Hormone Resistance and was found to segregate with the disease phenotype in this family in an autosomal dominant pattern (Rivolta_2009, Chiesa_2012). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant had a reduced affinity for T3 and resulted in a decreased induction of expression from T3 response elements compared to the WT protein (Zavacki_1993). Additionally, several variants affecting the same amino acid (Pro453Ser, Pro453Thr, Pro453Ala) have been classified as pathogenic, suggesting Pro453 is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21870171, 19268523, 8264663). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |