ClinVar Genomic variation as it relates to human health
NM_000369.5(TSHR):c.1637G>A (p.Trp546Ter)
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.
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(7); Likely pathogenic(1); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000369.5(TSHR):c.1637G>A (p.Trp546Ter)
Variation ID: 6439 Accession: VCV000006439.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.1 14: 81143695 (GRCh38) [ NCBI UCSC ] 14: 81610039 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 1, 2015 Sep 29, 2024 Aug 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000369.5:c.1637G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000360.2:p.Trp546Ter nonsense NM_000369.3:c.1637G>A NC_000014.9:g.81143695G>A NC_000014.8:g.81610039G>A NG_009206.1:g.193171G>A LRG_523:g.193171G>A LRG_523t1:c.1637G>A LRG_523p1:p.Trp546Ter - Protein change
- W546*
- Other names
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- Canonical SPDI
- NC_000014.9:81143694:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD) 0.00021
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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TSHR | - | - |
GRCh38 GRCh37 |
493 | 551 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000006809.10 | |
Benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000292905.6 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2024 | RCV000333686.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2021 | RCV002512852.2 | |
TSHR-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 7, 2023 | RCV004528087.1 |
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
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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
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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. |
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Pathogenic
(Sep 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069239.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the TSHR gene demonstrated a sequence change, c.1637G>A in exon 10, which results in the creation of a premature stop codon … (more)
DNA sequence analysis of the TSHR gene demonstrated a sequence change, c.1637G>A in exon 10, which results in the creation of a premature stop codon at amino acid position 546, p.Trp546*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHR protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous state in patients with congenital hypothyroidism (PMIDs: 12629076, 14725684). Functional studies have also demonstrated reduced expression of receptors on the cell surface and decreased binding affinity in cells transiently transfected with the p.Trp546* sequence change (PMID: 9100579). (less)
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Likely pathogenic
(Feb 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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TSHR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103207.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TSHR c.1637G>A variant is predicted to result in premature protein termination (p.Trp546*). This variant has been reported in the homozygous and compound heterozygous states … (more)
The TSHR c.1637G>A variant is predicted to result in premature protein termination (p.Trp546*). This variant has been reported in the homozygous and compound heterozygous states in individuals with congenital hypothyroidism and thyroid hormone resistance (Clifton-Bligh et al. 1997. PubMed ID: 9100579; Jordan et al. 2003. PubMed ID: 12629076; Park et al. 2004. PubMed ID: 14725684). A heterozygous carrier in one study was also found to have abnormal thyroid function (Park et al. 2004. PubMed ID: 14725684). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-81610039-G-A). Nonsense variants in TSHR are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Dec 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238384.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypothyroidism due to TSH receptor mutations
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803522.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: TSHR c.1637G>A (p.Trp546X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TSHR c.1637G>A (p.Trp546X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 251346 control chromosomes. c.1637G>A has been reported in the literature in multiple individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. Jordan_2003, deRoux_1996, Clifton_Bligh_1997). 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 indicating reduced surface receptor expression and negligible binding activity(Clifton_Bligh_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9100579, 12629076, 8954020). ClinVar contains an entry for this variant (Variation ID: 6439). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329922.11
First in ClinVar: Dec 06, 2016 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate that this variant results in a nonfunctional protein, with negligible membrane radioligand binding (PMID: 9100579); Nonsense variant predicted to result in … (more)
Published functional studies demonstrate that this variant results in a nonfunctional protein, with negligible membrane radioligand binding (PMID: 9100579); Nonsense variant predicted to result in protein truncation, as the last 219 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 14725684, 15863666, 12629076, 27637299, 30665703, 34308104, 29625052, 34200080, 34662886, 35177841, 36451132, 8954020, 9100579) (less)
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypothyroidism due to TSH receptor mutations
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000389149.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TSHR c.1637G>A (p.Trp546Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp546Ter variant has … (more)
The TSHR c.1637G>A (p.Trp546Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp546Ter variant has been reported in at least four studies in which it is found in a total of six patients with congenital hypothyroidism including in two in a homozygous state and in four in a compound heterozygous state, all with a second missense variant (de Roux et al. 1996; Clifton-Bligh et al. 1997; Jordan et al. 2003; Park et al. 2004). The p.Trp546Ter variant was found in two of 368 controls and is reported at a frequency of 0.00058 in the European-American population of the Exome Sequencing Project. Functional studies in COS-7 and JEG3 cells demonstrated reduced expression of receptors on the cell surface and decreased binding affinity in cells transiently transfected with the p.Trp546Ter variant (de Roux et al. 1996; Clifton-Bligh et al. 1997). Based on the collective evidence and the potential impact of stop-gained variants, the p.Trp546Ter variant is classified as pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial hyperthyroidism due to mutations in TSH receptor
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000389148.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001214235.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp546*) in the TSHR gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Trp546*) in the TSHR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acid(s) of the TSHR protein. This variant is present in population databases (rs121908866, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with thyroid-stimulating hormone (TSH) resistance and autosomal recessive congenital hypothyroidism (PMID: 8954020, 9100579, 12629076, 14725684). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6439). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHR function (PMID: 9100579). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003699147.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1637G>A (p.W546*) alteration, located in exon 10 (coding exon 10) of the TSHR gene, consists of a G to A substitution at nucleotide position … (more)
The c.1637G>A (p.W546*) alteration, located in exon 10 (coding exon 10) of the TSHR gene, consists of a G to A substitution at nucleotide position 1637. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 546. Although biallelic loss of function alterations in TSHR have been associated with congenital nongoitrous hypothyroidism, haploinsufficiency for TSHR has not been established as a mechanism of disease for nonautoimmune hyperthyroidism. Based on the available evidence, the TSHR c.1637G>A (p.W546*) alteration is classified as pathogenic for autosomal recessive congenital nongoitrous hypothyroidism; however, it is unlikely to be causative of autosomal dominant nonautoimmune hyperthyroidism. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (31/282748) total alleles studied. The highest observed frequency was 0.02% (28/129080) of European (non-Finnish) alleles. This alteration has been detected in both homozygous and compound heterozygous states in individuals with autosomal recessive congenital hypothyroidism (Biebermann, 2012; Clifton-Bligh, 1997; Jordan, 2003; Park, 2004). Functional studies showed that cells transiently transfected with this mutation have nonfunctional TSH receptor with negligible membrane radioligand binding (Clifton-Bligh, 1997). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 01, 2003)
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no assertion criteria provided
Method: literature only
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HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027005.3
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015 |
Comment on evidence:
For discussion of the trp546-to-ter (W546X) mutation in the TSHR gene that was found in compound heterozygous state in a patient with congenital hypothyroidism (CHNG1; … (more)
For discussion of the trp546-to-ter (W546X) mutation in the TSHR gene that was found in compound heterozygous state in a patient with congenital hypothyroidism (CHNG1; 275200) by Clifton-Bligh et al. (1997), see 603372.0009. Jordan et al. (2003) reported 2 Welsh sibs with congenital hypothyroidism identified by neonatal screening. Both had normal-sized and placed glands but negative isotope uptake. Both sibs were homozygous for the W546X mutation in the fourth membrane spanning region of the TSHR protein. The euthyroid parents were heterozygous for the mutation and unrelated. Jordan et al. (2003) noted that the W546X had been described in 3 additional families (1 of them Welsh), suggesting that it may be a relatively common mutation. Jordan et al. (2003) genotyped 368 euthyroid Welsh individuals using single-nucleotide primer extension, and found 366 homozygous wildtype and 2 heterozygous for the mutation. Jordan et al. (2003) suggested that the W546X mutation may be a major contributor to hypothyroidism in the Welsh population. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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New pathogenic thyrotropin receptor mutations decipher differentiated activity switching at a conserved helix 6 motif of family A GPCR. | Biebermann H | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22112806 |
W546X mutation of the thyrotropin receptor causes subclinical hypothyroidism in various clinical settings. | Locantore P | Clinical endocrinology | 2007 | PMID: 17524032 |
Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor. | Park SM | Clinical endocrinology | 2004 | PMID: 14725684 |
The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population. | Jordan N | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12629076 |
Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. | Clifton-Bligh RJ | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9100579 |
Four families with loss of function mutations of the thyrotropin receptor. | de Roux N | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8954020 |
Text-mined citations for rs121908866 ...
HelpRecord 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.