chr3-24122946-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001354712.2(THRB):c.1324A>G(p.Met442Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
THRB
NM_001354712.2 missense
NM_001354712.2 missense
Scores
8
5
6
Clinical Significance
Conservation
PhyloP100: 6.22
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 gene, where missense usually causes diseases (based on misZ statistic), THRB. . Gene score misZ: 2.5652 (greater than the threshold 3.09). Trascript score misZ: 3.708 (greater than threshold 3.09). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. GenCC has associacion of the gene with 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, 0.91
PP5
Variant 3-24122946-T-C is Pathogenic according to our data. Variant chr3-24122946-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| THRB | NM_001354712.2 | c.1324A>G | p.Met442Val | missense_variant | 11/11 | ENST00000646209.2 | NP_001341641.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 27, 2022 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with resistance to thyroid hormone (RTH) (PMIDs: 1661299 (1991) and 21871106 (2011)). Functional studies report the variant is damaging to protein function (PMIDs: 1661299 (1991) and 2555064 (1989)). 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 likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2023 | Observed in two siblings with generalized thyroid hormone resistance (Parrilla et al., 1991); Published functional studies demonstrate a damaging effect resulting in reduction of binding affinity of the THRB receptor (Parrilla et al., 1991); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 2555064, 8013151, 19378427, 1661299, 21871106) - |
Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2022 | Variant summary: THRB c.1324A>G (p.Met442Val) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.1324A>G has been reported in the literature in individuals affected with Thyroid Hormone Resistance, Generalized or pituitary-selective. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1994 | - - |
THRB-related disorder Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 03, 2023 | The THRB c.1324A>G variant is predicted to result in the amino acid substitution p.Met442Val. This variant has been observed in multiple patients with thyroid hormone resistance (THR) (see, for example, Ono et al. 1991. PubMed ID: 1682340; Adams et al. 1994. PubMed ID: 8040303; Grace et al. 1995. PubMed ID: 8535442). Additionally, another substitution at the same amino acid (p.Met442Thr) has been shown to be causative for THR (Bayer et al. 2004. PubMed ID: 15031774; Pongjantarasatian. 2012. PubMed ID: 21795843). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Based on these observations, this variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D;D;D;D;D;D;D;D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;.;.;.;.;.;.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;L;L;L;L;L;L;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;.;.;.;.;.;.;N;.;N
REVEL
Pathogenic
Sift
Benign
T;T;.;.;.;.;.;.;T;.;T
Sift4G
Benign
T;T;.;.;.;.;.;.;T;.;T
Polyphen
P;P;P;P;P;P;P;P;P;P;.
Vest4
MutPred
Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);.;
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