ClinVar Miner

Submissions for variant NM_001354712.2(THRB):c.1354C>T (p.Pro452Ser)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion RCV002283791 SCV002572878 likely pathogenic Thyroid hormone resistance, generalized, autosomal dominant 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with THRB-related disorder (PMID: 29262478). Different missense changes at the same codon (p.Pro452Arg, p.Pro452Leu) have been reported to be associated with THRB-related disorder (PMID: 24722129 , 27168936). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987991 SCV004803680 uncertain significance not specified 2024-01-23 criteria provided, single submitter clinical testing Variant summary: THRB c.1354C>T (p.Pro452Ser) results in a non-conservative amino acid change located in the Nuclear hormone receptor, 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 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1354C>T has been reported in the literature in at least one individual affected with Thyroid Hormone Resistance (Sun_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29262478). ClinVar contains an entry for this variant (Variation ID: 1705477). Based on the evidence outlined above, the variant was classified as uncertain significance.

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