It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant was reported in multiple families who were affected with resistance to thyroid hormone (RTH), including those with a mild phenotype (PMIDs: 1314846 (1992), 23926384 (2010), and 25040256 (2014)). Functional studies have shown that this variant is associated with decreased T3 binding affinity (PMIDs: 1314846 (1992)) and 25040256 (2014)). Based on the available information, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001354712.2(THRB):c.959G>A (p.Arg320His)
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.
(7)
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001354712.2(THRB):c.959G>A (p.Arg320His)
Variation ID: 12553 Accession: VCV000012553.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p24.2 3: 24127684 (GRCh38) [ NCBI UCSC ] 3: 24169175 (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 Apr 4, 2013 Oct 8, 2024 Nov 28, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001354712.2:c.959G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001341641.1:p.Arg320His missense NM_000461.5:c.959G>A NP_000452.2:p.Arg320His missense NM_001128176.3:c.959G>A NP_001121648.1:p.Arg320His missense NM_001128177.2:c.959G>A NP_001121649.1:p.Arg320His missense NM_001252634.2:c.959G>A NP_001239563.1:p.Arg320His missense NM_001354708.2:c.959G>A NP_001341637.1:p.Arg320His missense NM_001354709.2:c.959G>A NP_001341638.1:p.Arg320His missense NM_001354710.2:c.959G>A NP_001341639.1:p.Arg320His missense NM_001354711.2:c.959G>A NP_001341640.1:p.Arg320His missense NM_001354713.2:c.959G>A NP_001341642.1:p.Arg320His missense NM_001354714.2:c.866G>A NP_001341643.1:p.Arg289His missense NM_001354715.2:c.866G>A NP_001341644.1:p.Arg289His missense NC_000003.12:g.24127684C>T NC_000003.11:g.24169175C>T NG_009159.1:g.372139G>A P10828:p.Arg320His - Protein change
- R320H, R289H
- Other names
- -
- Canonical SPDI
- NC_000003.12:24127683:C:T
-
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.
- -
- 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 |
323 | 367 | |
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) |
no assertion criteria provided
|
Oct 12, 2012 | RCV000013380.18 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 2, 2015 | RCV000622278.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 28, 2023 | RCV000760097.6 | |
|
THRB-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 19, 2024 | RCV004754258.1 |
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
(Jun 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889877.3
First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024 |
Comment:
It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant was reported in multiple families who were affected … (more)
It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant was reported in multiple families who were affected with resistance to thyroid hormone (RTH), including those with a mild phenotype (PMIDs: 1314846 (1992), 23926384 (2010), and 25040256 (2014)). Functional studies have shown that this variant is associated with decreased T3 binding affinity (PMIDs: 1314846 (1992)) and 25040256 (2014)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Feb 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740779.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Arachnodactyly (present) , Asymmetry of the thorax (present) , Increased arm span (present) , Dental crowding (present) , High, narrow palate (present) , Scoliosis (present) … (more)
Arachnodactyly (present) , Asymmetry of the thorax (present) , Increased arm span (present) , Dental crowding (present) , High, narrow palate (present) , Scoliosis (present) , Kyphosis (present) , Pes planus (present) , Joint hypermobility (present) , Torticollis (present) , Facial asymmetry (present) , Aortic root dilatation (present) , Dermal translucency (present) , Facial telangiectasia in butterfly midface distribution (present) , Tachycardia (present) , Syncope (present) , Hypertensive disorder (present) , Venous insufficiency (present) , Prominent superficial blood vessels (present) , Myopia (disease) (present) , Visual loss (present) , Spontaneous pneumothorax (present) , Recurrent urinary tract infections (present) , Urinary incontinence (present) , Conductive hearing impairment (present) , Abnormality of thyroid physiology (present) , Cholesteatoma (disease) (present) , Arnold-Chiari type I malformation (present) , Dilatation of the cerebral artery (present) , Tortuous cerebral arteries (present) , Headache (present) , Seizures (present) , Memory impairment (present) , Vertigo (present) , Peripheral neuropathy (present) , Abnormality of connective tissue (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Jul 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004021608.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Published functional studies demonstrate a reduction in T3 binding affinity for the R320H variant (Macchia et al., 2014); Not observed at significant frequency in large … (more)
Published functional studies demonstrate a reduction in T3 binding affinity for the R320H variant (Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25040256, 8514853, 23926384, 16053391, 34860176, 36531240, 33524107) (less)
|
|
|
Pathogenic
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198789.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Jun 01, 1993)
|
no assertion criteria provided
Method: literature only
|
THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033627.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 17, 2021 |
Comment on evidence:
Cugini et al. (1992) described autosomal dominant generalized thyroid hormone resistance (GRTHD; 188570) due to a guanine-to-adenine transition at nucleotide 1244, resulting in a change … (more)
Cugini et al. (1992) described autosomal dominant generalized thyroid hormone resistance (GRTHD; 188570) due to a guanine-to-adenine transition at nucleotide 1244, resulting in a change of arginine-315 to histidine (ARG315HIS). Affected members of this kindred appeared to have a relatively mild degree of resistance, with mean total thyroxine of only 192 +/- 24 nmol/L and inappropriately normal TSH levels. The oldest affected member studied was 62. The mutation was located further upstream than most previously described mutations; only ala312 to thr was further upstream. Weiss et al. (1993) found this mutation (designated arg320 to his in the new nomenclature) in 2 separate families with GRTHD. The distinctness of the mutant allele in the 2 families was supported by the fact that each was associated with a different CA repeat polymorphism. The change was a G-to-A transition at nucleotide 1244 in exon 9. (less)
|
|
|
Pathogenic
(Aug 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
THRB-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005361424.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The THRB c.959G>A variant is predicted to result in the amino acid substitution p.Arg320His. This variant has been reported to be causative for autosomal dominant … (more)
The THRB c.959G>A variant is predicted to result in the amino acid substitution p.Arg320His. This variant has been reported to be causative for autosomal dominant thyroid hormone resistance (Weiss et al. 1993. PubMed ID: 8514853; Narumi et al. 2010. PubMed ID: 23926384; Macchia et al. 2014. PubMed ID: 25040256). Other substitutions at this same amino acid (p.Arg320Ser, p.Arg320Cys, and p.Arg320Leu) have also been found in patients with thyroid hormone resistance (Amor et al. 2014, PubMed ID: 24722129; Burman et al. 1992. PubMed ID: 1358935; Adams et al. 1994. PubMed ID: 8040303). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Oct 12, 2012)
|
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: SCV000692418.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
Comment:
Comment:
Published functional studies demonstrate a reduction in T3 binding affinity for the R320H variant (Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25040256, 8514853, 23926384, 16053391, 34860176, 36531240, 33524107)
Comment:
The THRB c.959G>A variant is predicted to result in the amino acid substitution p.Arg320His. This variant has been reported to be causative for autosomal dominant thyroid hormone resistance (Weiss et al. 1993. PubMed ID: 8514853; Narumi et al. 2010. PubMed ID: 23926384; Macchia et al. 2014. PubMed ID: 25040256). Other substitutions at this same amino acid (p.Arg320Ser, p.Arg320Cys, and p.Arg320Leu) have also been found in patients with thyroid hormone resistance (Amor et al. 2014, PubMed ID: 24722129; Burman et al. 1992. PubMed ID: 1358935; Adams et al. 1994. PubMed ID: 8040303). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted 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:
It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant was reported in multiple families who were affected with resistance to thyroid hormone (RTH), including those with a mild phenotype (PMIDs: 1314846 (1992), 23926384 (2010), and 25040256 (2014)). Functional studies have shown that this variant is associated with decreased T3 binding affinity (PMIDs: 1314846 (1992)) and 25040256 (2014)). Based on the available information, this variant is classified as pathogenic.
Comment:
Published functional studies demonstrate a reduction in T3 binding affinity for the R320H variant (Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25040256, 8514853, 23926384, 16053391, 34860176, 36531240, 33524107)
Comment:
The THRB c.959G>A variant is predicted to result in the amino acid substitution p.Arg320His. This variant has been reported to be causative for autosomal dominant thyroid hormone resistance (Weiss et al. 1993. PubMed ID: 8514853; Narumi et al. 2010. PubMed ID: 23926384; Macchia et al. 2014. PubMed ID: 25040256). Other substitutions at this same amino acid (p.Arg320Ser, p.Arg320Cys, and p.Arg320Leu) have also been found in patients with thyroid hormone resistance (Amor et al. 2014, PubMed ID: 24722129; Burman et al. 1992. PubMed ID: 1358935; Adams et al. 1994. PubMed ID: 8040303). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction. | Narumi S | Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology | 2010 | PMID: 23926384 |
| Resistance to thyroid hormone in a patient with thyroid dysgenesis. | Grasberger H | Thyroid : official journal of the American Thyroid Association | 2005 | PMID: 16053391 |
| Ligand binding and nuclear receptor evolution. | Escriva H | BioEssays : news and reviews in molecular, cellular and developmental biology | 2000 | PMID: 10918302 |
| Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. | Weiss RE | The Journal of clinical investigation | 1993 | PMID: 8514853 |
| An arginine to histidine mutation in codon 315 of the c-erbA beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3'-triiodothyronine binding activity. | Cugini CD Jr | The Journal of clinical endocrinology and metabolism | 1992 | PMID: 1314846 |
Text-mined citations for rs121918693 ...
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 Oct 13, 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.