rs1553609210
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_001354712.2(THRB):c.1286G>A(p.Arg429Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
THRB
NM_001354712.2 missense
NM_001354712.2 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
THRB (HGNC:11799): (thyroid hormone receptor beta) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, THRB
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
?
Variant 3-24122984-C-T is Pathogenic according to our data. Variant chr3-24122984-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 548123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-24122984-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THRB | NM_001354712.2 | c.1286G>A | p.Arg429Gln | missense_variant | 11/11 | ENST00000646209.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THRB | ENST00000646209.2 | c.1286G>A | p.Arg429Gln | missense_variant | 11/11 | NM_001354712.2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 31
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 27, 2022 | Variant summary: THRB c.1286G>A (p.Arg429Gln) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.1286G>A has been reported in the literature in multiple individuals affected with autosomal dominant generalized and pitutary Thyroid Hormone Resistance (example, Flynn_1994, Adams_1994, Taniyama_2001, Kong_2005, Abeal_2011, Dieu_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Flynn_1994, Adams_1994, Wei Wan_2005). The most pronounced variant effect results in approximately 20% of normal affinity for T3 hormone binding by the mutant receptors (Adams_1994). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | May 21, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 08, 2023 | The frequency of this variant in the general population, 0.0000066 (1/152132 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with resistance to thyroid hormone (RTH) (PMIDs: 8040303 (1994), 7528740 (1994), 11167935 (2001), 21703645 (2011), and 32635414 (2020)). Functional studies show damaging effects on homodimerization, protein-protein binding and gene repression (PMIDs: 7528740 (1994), 8040303 (1994), 10847591 (2000), 19439650 (2009), 21622532 (2011), and 25040256 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
THRB-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2024 | The THRB c.1286G>A variant is predicted to result in the amino acid substitution p.Arg429Gln. This variant has been reported in multiple patients with thyroid hormone resistance (Adams et al. 1994. PubMed ID: 8040303; Macchia et al. 2014. PubMed ID: 25040256). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D;D;D;D;D;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;.;.;.;.;.;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;.;.;D;.;D
Sift4G
Uncertain
D;D;.;.;.;.;.;.;D;.;D
Polyphen
D;D;D;D;D;D;D;D;D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at