Variant summary: THRB c.1312C>T (p.Arg438Cys) 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 251486 control chromosomes (gnomAD). c.1312C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance syndrome (examples: Adams_1994, Macchia_2014, and Toumba_2019). Additionally, in one family the variant was shown to co-segregate with the disease (Toumba_2019). These data indicate that the variant is associated with disease. Early lethality has been observed in mice when animals are homozygous for this variant in THRalpha (Tinnikov_2002). Functional studies in the mouse model and humans have demonstrated this variant does impair interactions with TR3 (examples: Macchia_2014 and Tinnikov_2002). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001354712.2(THRB):c.1312C>T (p.Arg438Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001354712.2(THRB):c.1312C>T (p.Arg438Cys)
Variation ID: 492921 Accession: VCV000492921.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.2 3: 24122958 (GRCh38) [ NCBI UCSC ] 3: 24164449 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 19, 2018 Nov 20, 2023 Jun 12, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001354712.2:c.1312C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001341641.1:p.Arg438Cys missense NM_000461.5:c.1312C>T NP_000452.2:p.Arg438Cys missense NM_001128176.3:c.1312C>T NP_001121648.1:p.Arg438Cys missense NM_001128177.2:c.1312C>T NP_001121649.1:p.Arg438Cys missense NM_001252634.2:c.1312C>T NP_001239563.1:p.Arg438Cys missense NM_001354708.2:c.1312C>T NP_001341637.1:p.Arg438Cys missense NM_001354709.2:c.1312C>T NP_001341638.1:p.Arg438Cys missense NM_001354710.2:c.1312C>T NP_001341639.1:p.Arg438Cys missense NM_001354711.2:c.1312C>T NP_001341640.1:p.Arg438Cys missense NM_001354713.2:c.1312C>T NP_001341642.1:p.Arg438Cys missense NM_001354714.2:c.1219C>T NP_001341643.1:p.Arg407Cys missense NM_001354715.2:c.1219C>T NP_001341644.1:p.Arg407Cys missense NC_000003.12:g.24122958G>A NC_000003.11:g.24164449G>A NG_009159.1:g.376865C>T - Protein change
- R438C, R407C
- Other names
- -
- Canonical SPDI
- NC_000003.12:24122957:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| THRB | - | - |
GRCh38 GRCh37 |
325 | 369 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 17, 2021 | RCV000584262.2 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jun 10, 2022 | RCV002469212.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 12, 2023 | RCV003389056.1 | |
|
THRB-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2022 | RCV003392424.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Thyroid hormone resistance, generalized, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002051188.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: THRB c.1312C>T (p.Arg438Cys) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein … (more)
Variant summary: THRB c.1312C>T (p.Arg438Cys) 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 251486 control chromosomes (gnomAD). c.1312C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance syndrome (examples: Adams_1994, Macchia_2014, and Toumba_2019). Additionally, in one family the variant was shown to co-segregate with the disease (Toumba_2019). These data indicate that the variant is associated with disease. Early lethality has been observed in mice when animals are homozygous for this variant in THRalpha (Tinnikov_2002). Functional studies in the mouse model and humans have demonstrated this variant does impair interactions with TR3 (examples: Macchia_2014 and Tinnikov_2002). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Uncertain significance
(Jun 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002765263.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest that this variant results in a reduction of T3 binding affinity (Tinnikov et al., 2002; Macchia et al., 2014); Reported in association with THRB-related resistance to thyroid hormone syndrome (Adams et al., 1994; Macchia et al., 2014; Toumba et al., 2019); This variant is associated with the following publications: (PMID: 25040256, 12356724, 8040303, 32581500) (less)
|
|
|
Pathogenic
(Jun 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774377.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
In the published literature, this variant has been reported in families with resistance to thyroid hormone and functional studies indicated abnormal hormone binding and cofactor … (more)
In the published literature, this variant has been reported in families with resistance to thyroid hormone and functional studies indicated abnormal hormone binding and cofactor dissociation (PMIDs: 8040303 (1994), 9092799 (1997), 12356724 (2002), and 20237409 (2010)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Jun 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV004101147.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
|
|
|
Pathogenic
(Oct 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
THRB-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004121036.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The THRB c.1312C>T variant is predicted to result in the amino acid substitution p.Arg438Cys. This variant was reported in the heterozygous state in multiple individuals … (more)
The THRB c.1312C>T variant is predicted to result in the amino acid substitution p.Arg438Cys. This variant was reported in the heterozygous state in multiple individuals with thyroid hormone resistance (Adams et al. 1994. PubMed ID: 8040303; Macchia et al. 2014. PubMed ID: 25040256; Toumba et al. 2019. PubMed ID: 32581500). Functional analysis of this variant showed that it lead to an impairment of dissociation from corepressors in the presence of thyroid hormone (Yoh et al. 1997. PubMed ID: 9092799). Mouse models of this variant exhibited lowered serum T3 ant T4 levels with growth delay during neonatal period (variant referred to as p.Arg384 in mouse, Ortiga-Carvalho et al. 2014. PubMed ID: 25135573). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note other variants impacting the same amino acid (p.Arg438His and p.Arg438Pro) has also been reported in patients with thyroid hormone resistance (Han et al. 2015. PubMed ID: 26041374; Cardoso et al. 2014. PubMed ID: 25063548; Esquiaveto-Aun et al. 2015. PubMed ID: 25738994). Based on this evidence, we interpret the c.1312C>T (p.Arg438Cys) variant as pathogenic. (less)
|
|
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Pathogenic
(Jan 28, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Thyroid hormone resistance, generalized, autosomal dominant
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692429.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest that this variant results in a reduction of T3 binding affinity (Tinnikov et al., 2002; Macchia et al., 2014); Reported in association with THRB-related resistance to thyroid hormone syndrome (Adams et al., 1994; Macchia et al., 2014; Toumba et al., 2019); This variant is associated with the following publications: (PMID: 25040256, 12356724, 8040303, 32581500)
Comment:
In the published literature, this variant has been reported in families with resistance to thyroid hormone and functional studies indicated abnormal hormone binding and cofactor dissociation (PMIDs: 8040303 (1994), 9092799 (1997), 12356724 (2002), and 20237409 (2010)). Based on the available information, this variant is classified as pathogenic.
Comment:
The THRB c.1312C>T variant is predicted to result in the amino acid substitution p.Arg438Cys. This variant was reported in the heterozygous state in multiple individuals with thyroid hormone resistance (Adams et al. 1994. PubMed ID: 8040303; Macchia et al. 2014. PubMed ID: 25040256; Toumba et al. 2019. PubMed ID: 32581500). Functional analysis of this variant showed that it lead to an impairment of dissociation from corepressors in the presence of thyroid hormone (Yoh et al. 1997. PubMed ID: 9092799). Mouse models of this variant exhibited lowered serum T3 ant T4 levels with growth delay during neonatal period (variant referred to as p.Arg384 in mouse, Ortiga-Carvalho et al. 2014. PubMed ID: 25135573). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note other variants impacting the same amino acid (p.Arg438His and p.Arg438Pro) has also been reported in patients with thyroid hormone resistance (Han et al. 2015. PubMed ID: 26041374; Cardoso et al. 2014. PubMed ID: 25063548; Esquiaveto-Aun et al. 2015. PubMed ID: 25738994). Based on this evidence, we interpret the c.1312C>T (p.Arg438Cys) variant as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: THRB c.1312C>T (p.Arg438Cys) 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 251486 control chromosomes (gnomAD). c.1312C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance syndrome (examples: Adams_1994, Macchia_2014, and Toumba_2019). Additionally, in one family the variant was shown to co-segregate with the disease (Toumba_2019). These data indicate that the variant is associated with disease. Early lethality has been observed in mice when animals are homozygous for this variant in THRalpha (Tinnikov_2002). Functional studies in the mouse model and humans have demonstrated this variant does impair interactions with TR3 (examples: Macchia_2014 and Tinnikov_2002). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest that this variant results in a reduction of T3 binding affinity (Tinnikov et al., 2002; Macchia et al., 2014); Reported in association with THRB-related resistance to thyroid hormone syndrome (Adams et al., 1994; Macchia et al., 2014; Toumba et al., 2019); This variant is associated with the following publications: (PMID: 25040256, 12356724, 8040303, 32581500)
Comment:
In the published literature, this variant has been reported in families with resistance to thyroid hormone and functional studies indicated abnormal hormone binding and cofactor dissociation (PMIDs: 8040303 (1994), 9092799 (1997), 12356724 (2002), and 20237409 (2010)). Based on the available information, this variant is classified as pathogenic.
Comment:
The THRB c.1312C>T variant is predicted to result in the amino acid substitution p.Arg438Cys. This variant was reported in the heterozygous state in multiple individuals with thyroid hormone resistance (Adams et al. 1994. PubMed ID: 8040303; Macchia et al. 2014. PubMed ID: 25040256; Toumba et al. 2019. PubMed ID: 32581500). Functional analysis of this variant showed that it lead to an impairment of dissociation from corepressors in the presence of thyroid hormone (Yoh et al. 1997. PubMed ID: 9092799). Mouse models of this variant exhibited lowered serum T3 ant T4 levels with growth delay during neonatal period (variant referred to as p.Arg384 in mouse, Ortiga-Carvalho et al. 2014. PubMed ID: 25135573). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note other variants impacting the same amino acid (p.Arg438His and p.Arg438Pro) has also been reported in patients with thyroid hormone resistance (Han et al. 2015. PubMed ID: 26041374; Cardoso et al. 2014. PubMed ID: 25063548; Esquiaveto-Aun et al. 2015. PubMed ID: 25738994). Based on this evidence, we interpret the c.1312C>T (p.Arg438Cys) variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotype variability and different genotype of four patients with thyroid hormone resistance syndrome due to variants in the THRB gene. | Toumba M | Hippokratia | 2019 | PMID: 32581500 |
| Thyroid hormone receptors and resistance to thyroid hormone disorders. | Ortiga-Carvalho TM | Nature reviews. Endocrinology | 2014 | PMID: 25135573 |
| Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor β. | Macchia E | Clinical endocrinology | 2014 | PMID: 25040256 |
| Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. | Mitchell CS | The Journal of clinical investigation | 2010 | PMID: 20237409 |
| Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. | Tinnikov A | The EMBO journal | 2002 | PMID: 12356724 |
| Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. | Yoh SM | Molecular endocrinology (Baltimore, Md.) | 1997 | PMID: 9092799 |
| Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene. | Adams M | The Journal of clinical investigation | 1994 | PMID: 8040303 |
Text-mined citations for rs367757240 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.