Table 2.
Patients with RTH carrying newly described THRB germline variants. Variant features, population database report, in silico predictions of pathogenicity, as well as American College of Medical Genetics and Genomics (ACMG) classification of the newly described THRB variants.
| EXON | HGVSc1 NM_000461.4 | HGVSp2 NP_000452.2 | RS ID | gnomAD | Families | Patients | In Silico Predictions Algorithms | Classification Following ACMG |
|---|---|---|---|---|---|---|---|---|
| 8 | c.790G > T | p.(Val264Phe) | rs1559415493 | 0 | 1 | 1 | 7 pathogenic vs. 1 benign * | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 8 | c.793G > T | p.(Asp265Tyr) | none | 0 | 1 | 1 | 7 pathogenic vs. 1 benign * | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 8 | c.805T > G | p.(Phe269Val) | none | 0 | 1 | 2 | 8 pathogenic ** | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 8 | c.815T > G | p.(Phe272Cys) | none | 0 | 1 | 4 | 7 pathogenic vs. 1 benign * | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 9 | c.920G > A | p.(Gly307Asp) | rs1553611101 | 0 | 1 | 1 | 8 pathogenic ** | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 9 | c.985A > T | p(.Thr329Ser) | none | 0 | 1 | 1 | 7 pathogenic vs. 1 benign *** | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 9 | c.993T > A | p.(Asn331Lys) | none | 0 | 1 | 1 | 6 pathogenic vs. 2 benign **** | Likely pathogenic (PM1, PM2, PP2, PP3, PM5) |
| 9 | c.1058T > C | p.(Ile353Thr) | none | 0 | 4 | 7 | 8 pathogenic ** | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 9 | c.1057A > T | p.(Ile353Phe) | none | 0 | 1 | 1 | 8 pathogenic ** | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 10 | c.1334A > G | p.(Glu445Gly) | none | 0 | 1 | 2 | 8 pathogenic ** | Likely pathogenic (PM1, PM2, PP2, PP3) |
| 10 | c.1370A > C ***** | p.(Glu457Ala) ***** | none | 0 | 1 | 1 | 8 pathogenic ** | Likely pathogenic (PM1, PM2, PP2, PP3) |
In gray, figures variants found in our center, already published in “Annales d’Endocrinologie”, a French journal, but not found in Pubmed (C. Bournaud, F. Savagner, F. Borson-Chazot, O. Revol, M. Oliel, S. Achard, Y. Malthiery, J. Orgiazzi, P. Rodien, Annales d’Endocrinologie Vol 66, N° 5, octobre 2005 p. 505 Doi:AE-10-2005-66-5-0003-4266-101019-200505896 and H. Combe, I. Khochtali, H. Bihan, P. Rodien, R. Cohen, F. Savagner, Annales d’Endocrinologie Vol 66, N° 5, octobre 2005 pp. 505–506 Doi:AE-10-2005-66-5-0003-4266-101019-200505897). Two variants had an already existing RS ID but without associated publication(s). 1 Human Genome Variation Society DNA nomenclature. 2 Human Genome Variation Society protein nomenclature. * Seven pathogenic predictions from DANN, FATHMM, LRT, MutationTaster, PROVEAN, FATHMM-MKL, and SIFT vs. one benign prediction from MutationAssessor. ** Eight pathogenic predictions from DANN, FATHMM, LRT, MutationAssessor, MutationTaster, PROVEAN, FATHMM-MKL, and SIFT. *** Seven pathogenic predictions from DANN, FATHMM, MutationAssessor, MutationTaster, PROVEAN, FATHMM-MKL, and SIFT vs. one benign prediction from LRT. **** Six pathogenic predictions from DANN, FATHMM, LRT, MutationTaster, FATHMM-MKL, and SIFT vs. two benign predictions from MutationAssessor and PROVEAN NA: Not Applicable. ***** Variant already described in an abstract (Chatterjee K, Adams M, Collingwood T, Matthews C, Rajanayagam O. “Functional analysis of mutant thyroid hormone receptors in thyroid hormone resistance syndrome”, Second International Workshop on Thyroid Hormone Resistance, 1995; Padua, Italy) but not indexed in Medline nor found in Pubmed. PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP2: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.