ClinVar Genomic variation as it relates to human health
NM_000369.5(TSHR):c.1657G>A (p.Ala553Thr)
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(2); Likely pathogenic(3); Likely 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.1657G>A (p.Ala553Thr)
Variation ID: 6445 Accession: VCV000006445.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.1 14: 81143715 (GRCh38) [ NCBI UCSC ] 14: 81610059 (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 Oct 11, 2015 Mar 16, 2024 Feb 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000369.5:c.1657G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000360.2:p.Ala553Thr missense NC_000014.9:g.81143715G>A NC_000014.8:g.81610059G>A NG_009206.1:g.193191G>A LRG_523:g.193191G>A LRG_523t1:c.1657G>A LRG_523p1:p.Ala553Thr - Protein change
- A553T
- Other names
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- Canonical SPDI
- NC_000014.9:81143714: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 |
470 | 524 |
Conditions - Germline
Condition
Help
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
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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV000006815.14 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000314691.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2021 | RCV002512853.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV003764533.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2024 | RCV003924806.1 |
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
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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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Likely pathogenic
(Nov 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypothyroidism, congenital, nongoitrous, 1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000597611.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Likely 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: SCV000389150.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TSHR c.1657G>A (p.Ala553Thr) missense variant is described in five studies in which it is identified in seven patients with congenital hyopthyroidism including in a … (more)
The TSHR c.1657G>A (p.Ala553Thr) missense variant is described in five studies in which it is identified in seven patients with congenital hyopthyroidism including in a homozygous state in two pairs of consanguineous siblings and in a compound heterozygous state in two non-consanguineous siblings and an additional unrelated patient (Abramowicz et al. 1997; Park et al. 2004; Cangul et al. 2010; Cangul et al. 2012; van Tellingen et al. 2016). The variant was absent from 400 control alleles but is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated that the p.Ala553Thr variant resulted in extremely low cell-surface expression of the receptor compared to wild type (Abramowicz et al. 1997). The Ala553 residue is highly conserved (Abramowicz et al. 1997; Cangul et al. 2010). Stability studies showed that the variant was expected to be significantly destabilizing for the protein (Cangul et al. 2010). Based on the collective evidence, the p.Ala553Thr variant is classified as likely 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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Likely 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: SCV000389151.3
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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Pathogenic
(Dec 26, 2023)
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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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Invitae
Accession: SCV004678595.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 553 of the TSHR protein (p.Ala553Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 553 of the TSHR protein (p.Ala553Thr). This variant is present in population databases (rs121908872, gnomAD 0.006%). This missense change has been observed in individual(s) with hypothyroidism (PMID: 9185526, 14725684, 20718767, 27255745, 29092890). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6445). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TSHR function (PMID: 9185526, 10560953). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 02, 2024)
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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: SCV004745657.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TSHR c.1657G>A variant is predicted to result in the amino acid substitution p.Ala553Thr. This variant has been reported in the monoallelic or bi-allelic state … (more)
The TSHR c.1657G>A variant is predicted to result in the amino acid substitution p.Ala553Thr. This variant has been reported in the monoallelic or bi-allelic state in individuals with Hypothyroidism (Abramowicz et al. 1997. PubMed ID: 9185526; Park et al. 2004. PubMed ID: 14725684; Abe et al. 2017. PubMed ID: 29092890). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Sep 08, 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: SCV003737894.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.1657G>A (p.A553T) alteration is located in exon 10 (coding exon 10) of the TSHR gene. This alteration results from a G to A substitution … (more)
The c.1657G>A (p.A553T) alteration is located in exon 10 (coding exon 10) of the TSHR gene. This alteration results from a G to A substitution at nucleotide position 1657, causing the alanine (A) at amino acid position 553 to be replaced by a threonine (T). Based on the available evidence, this variant is expected to be causative of congenital nongoitrous hypothyroidism (AR) when present along with a second pathogenic or likely pathogenic variant on the other allele; however, it is unlikely to be causative of nonautoimmune hyperthyroidism (AD). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (8/251360) total alleles studied. The highest observed frequency was 0.01% (2/30616) of South Asian alleles. This alteration has been detected in the homozygous state or compound heterozygous with a second TSHR variant in multiple unrelated individuals with congenital hypothyroidism (Abramowicz, 1997; Park, 2004; Cangul, 2010; van Tellingen, 2016). Heterozygous carriers of this variant have been reported with subclinical or mild hypothyroidism (Nicoletti, 2009; Abe, 2018). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 15, 1997)
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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: SCV000027011.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2018 |
Comment on evidence:
In a brother and sister, born of consanguineous parents, with congenital hypothyroidism (CHNG1; 275200), Abramowicz et al. (1997) identified a homozygous mutation in the TSHR … (more)
In a brother and sister, born of consanguineous parents, with congenital hypothyroidism (CHNG1; 275200), Abramowicz et al. (1997) identified a homozygous mutation in the TSHR gene, resulting in an ala553-to-thr (A553T) substitution in the fourth transmembrane domain of the protein. The mutation was heterozygous in both parents and 2 unaffected sibs. The patients were initially diagnosed with thyroid agenesis, but cervical ultrasonography in both patients revealed a very hypoplastic thyroid gland. Functional analysis in transfected COS-7 cells showed that the mutation resulted in extremely low expression at the cell surface as compared with the wildtype receptor, in spite of an apparently normal intracellular synthesis. Blood thyroglobulin was unexpectedly elevated in the patients at the time of diagnosis; Abramowicz et al. (1997) speculated as to the possible explanation for this seemingly paradoxical finding. (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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Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach. | Abe K | European journal of endocrinology | 2018 | PMID: 29092890 |
Poorly Controlled Congenital Hypothyroidism due to an Underlying Allgrove Syndrome. | van Tellingen V | Hormone research in paediatrics | 2016 | PMID: 27255745 |
TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis. | Cangul H | Journal of pediatric endocrinology & metabolism : JPEM | 2012 | PMID: 22876533 |
Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. | Cangul H | Clinical endocrinology | 2010 | PMID: 20718767 |
Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism. | Nicoletti A | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19820021 |
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 |
Structure-function relationships of two loss-of-function mutations of the thyrotropin receptor gene. | Costagliola S | Thyroid : official journal of the American Thyroid Association | 1999 | PMID: 10560953 |
Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. | Abramowicz MJ | The Journal of clinical investigation | 1997 | PMID: 9185526 |
Text-mined citations for rs121908872 ...
HelpRecord last updated Mar 17, 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.