chr3-24143511-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001354712.2(THRB):c.728G>A(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
THRB
NM_001354712.2 missense
NM_001354712.2 missense
Scores
13
2
4
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 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the THRB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.5652 (below the threshold of 3.09). Trascript score misZ: 3.708 (above the threshold of 3.09). GenCC associations: The gene is linked to thyroid hormone resistance, generalized, autosomal dominant, resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.913
PP5
Variant 3-24143511-C-T is Pathogenic according to our data. Variant chr3-24143511-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| THRB | NM_001354712.2 | c.728G>A | p.Arg243Gln | missense_variant | Exon 8 of 11 | ENST00000646209.2 | NP_001341641.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 exome
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1
AN:
1461864
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Cov.:
32
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1
AN XY:
727230
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jan 03, 2012 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1997 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2022 | Variant summary: THRB c.728G>A (p.Arg243Gln) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250376 control chromosomes. c.728G>A has been reported in the literature in multiple individuals affected with Generalized Autosomal Dominant Thyroid Hormone Resistance, (example, Chaves_2021). 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 (example, Yagi_1997). The most pronounced variant effect results in 16% of normal T3-dependent transactivation activity. This suggests that the receptor DNA-binding domain can modulate the function of the hormone-binding domain via allosteric mechanisms. 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. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 14, 2017 | - - |
Selective pituitary resistance to thyroid hormone;C2937288:Thyroid hormone resistance, generalized, autosomal dominant;C3489796:Thyroid hormone resistance, generalized, autosomal recessive Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 23, 2021 | - - |
THRB-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 01, 2024 | The THRB c.728G>A variant is predicted to result in the amino acid substitution p.Arg243Gln. This variant has been reported in heterozygous patients with resistance to thyroid hormone (see, for example, Yagi et al. 1997. PubMed ID: 9141558; Lado Abeal et al. 2011. PubMed ID: 21703645; 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
Uncertain
D;D;D;D;D;D;D;D;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;.;.;.;.;.;.;.;D;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;.
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;N;.;.;.;.;.;.;N;.;N
REVEL
Pathogenic
Sift
Benign
T;T;.;.;.;.;.;.;T;.;T
Sift4G
Benign
T;T;.;.;.;.;.;.;T;.;T
Polyphen
D;D;D;D;D;D;D;D;D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at