rs121918707
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001354712.2(THRB):c.727C>T(p.Arg243Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001354712.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THRB | NM_001354712.2 | c.727C>T | p.Arg243Trp | missense_variant | 8/11 | ENST00000646209.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THRB | ENST00000646209.2 | c.727C>T | p.Arg243Trp | missense_variant | 8/11 | NM_001354712.2 | |||
ENST00000702841.1 | n.83+5564G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74482
ClinVar
Submissions by phenotype
Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Sep 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2024 | Variant summary: THRB c.727C>T (p.Arg243Trp) 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 250638 control chromosomes. c.727C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (Pohlenz_1996, Glymph_2014, Pajek_2020) and observed to segregate with disease. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function indicate a significant affect on protein function (Shi_2014, Safer_1998). The following publications have been ascertained in the context of this evaluation (PMID: 33333891, 8664910, 9804773, 24174637, 26425626).ClinVar contains an entry for this variant (Variation ID: 12567). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 10, 2020 | The frequency of this variant in the general population, 0.000032 (1/31406 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been identified among a cohort of subjects with resistance to thyroid hormone (RTH) and has shown syndrome cosegregation (PMIDs: 8664910 (1996), 20237409 (2010), 26425626 (2014)). Furthermore, it has been identified as de novo and functional studies have shown it causes decreased ligand binding activity compared to the wild-type in a dominant negative manner (PMIDs: 9707435 (1998), 9804773 (1998), 24174637 (2014)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33333891, 9141558, 24174637, 9804773, 8664910, 20237409, 26425626) - |
THRB-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 23, 2024 | The THRB c.727C>T variant is predicted to result in the amino acid substitution p.Arg243Trp. This variant has been reported in multiple unrelated individuals with thyroid hormone resistance (Pohlenz et al. 1996. PubMed ID: 8664910; Safer et al. 1998. PubMed ID: 9804773; Shi et al. 2014. PubMed ID: 24174637). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at