VCV000225505.37 - ClinVar

NM_000369.5(TSHR):c.1349G>A (p.Arg450His)

Germline

Classification

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.

(10)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000369.5(TSHR):c.1349G>A (p.Arg450His)

Variation ID: 225505 Accession: VCV000225505.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q31.1 14: 81143407 (GRCh38) [ NCBI UCSC ] 14: 81609751 (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	Dec 6, 2016	Oct 20, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000369.5:c.1349G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000360.2:p.Arg450His	missense
NM_000369.3:c.1349G>A
NC_000014.9:g.81143407G>A
NC_000014.8:g.81609751G>A
NG_009206.1:g.192883G>A
LRG_523:g.192883G>A
LRG_523t1:c.1349G>A	LRG_523p1:p.Arg450His

... more HGVS ... less HGVS

Protein change

R450H

Other names

Canonical SPDI

NC_000014.9:81143406:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00014

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00023

Exome Aggregation Consortium (ExAC) 0.00029

Links

ClinGen: CA7294442 dbSNP: rs189261858 VarSome

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
Gene	OMIM	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.
TSHR		-	-	GRCh38 GRCh37	-	-

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.
Hypothyroidism due to TSH receptor mutations	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 13, 2021	RCV000490528.14
Congenital hypothyroidism	Pathogenic (1)	criteria provided, single submitter	Jul 17, 2018	RCV000826152.12
Ovarian cancer	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2022	RCV003153491.9
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000273881.34
Familial gestational hyperthyroidism	Pathogenic (1)	criteria provided, single submitter	Sep 16, 2022	RCV003225722.8

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 (Aug 15, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Hypothyroidism due to TSH receptor mutations Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915656.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (7) PubMed: 19506388‚ 27637299‚ 22405933‚ 21677043‚ 11442002‚ 15693879‚ 21707688 Comment: Across a selection of the available literature, the TSHR c.1349G>A (p.Arg450His) missense variant has been identified in a homozygous state in at least ten individuals … (more) Across a selection of the available literature, the TSHR c.1349G>A (p.Arg450His) missense variant has been identified in a homozygous state in at least ten individuals with congenital hypothyroidism, in a compound heterozygous state in at least four patients, and in a heterozygous state in ten patients in whom a second variant was not identified (Shibayama et al. 2005; Mizuno et al. 2009; Lee et al. 2011; Narumi et al. 2011; Chang et al. 2012; Fu et al. 2016). In at least one family, unaffected parents were identified as heterozygous carriers of the p.Arg450His variant. This variant was absent from 300 control chromosomes, but is reported at a frequency of 0.00335 in the East Asian population from the Exome Aggregation Consortium. In COS-7 cells, the p.Arg450His variant demonstrated slightly decreased cAMP production and slightly decreased TSH binding compared to wild type (Nagashima et al. 2001). In HEK293 cells, the p.Arg450His variant demonstrated 42% activity for Gs-coupled signaling and 8% activity for Gq-coupled signaling compared to wildtype (Narumi et al. 2011). Based on the collective evidence, the p.Arg450His 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)
Pathogenic (Jul 17, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Congenital hypothyroidism (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967686.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (16) PubMed: 28455095‚ 28444304‚ 27637299‚ 27084275‚ 26709262‚ 24895636‚ 23926367‚ 22405933‚ 21707688‚ 21677043‚ 21714469‚ 19506388‚ 19158199‚ 17526952‚ 15693879‚ 11442002 Comment: The p.Arg450His variant in TSHR has been reported in the homozygous or compound heterozygous state in >20 individuals with congenital hypothyroidism (Nagashima 2001, Shibayama 2005, … (more) The p.Arg450His variant in TSHR has been reported in the homozygous or compound heterozygous state in >20 individuals with congenital hypothyroidism (Nagashima 2001, Shibayama 2005, Kanda 2006, Narumi 2009, Mizuno 2009, Satoh 2009, Ma 2010, Lee 2011, Narumi 2011, Chang 2012, Tsunekawa 2014, Park 2016, Wang 2017). Heter ozygous family members frequently displayed subclinical hypothyroidism (Ma 2010, Narumi 2009, Kanda 2006, Nagashima 2001). A significant association between the p.Arg450His variant and the risk of congenital hypothyroidism has been observed in one study (Chang 2012). This variant has been identified in 0.26% (49/18868) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs189261858). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. In vitro functional studies provide some evidence that the p.Arg450H is variant may impact protein function (Nagashima 2001, Narumi 2009, Narumi 2011 ); however, these types of assays may not accurately represent biological functi on. Computational prediction tools and conservation analysis suggest that the p. Arg450His variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, this variant meets our criter ia to be classified as pathogenic for congenital hypothyroidism in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PP3; PS3_Supporting . (less) Number of individuals with the variant: 1
Pathogenic (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Hypothyroidism due to TSH receptor mutations Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267546.1 First in ClinVar: May 25, 2017 Last updated: May 25, 2017	Publications: PubMed (3) PubMed: 11442002‚ 22876533‚ 21714469 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Likely pathogenic (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ovarian cancer Affected status: yes Allele origin: germline	Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University Accession: SCV003843675.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023
Pathogenic (Sep 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial gestational hyperthyroidism Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807742.2 First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023	Comment: ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442345.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 11442002‚ 19506388‚ 21677043‚ 30083029‚ 31356790‚ 16756469 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the TSHR protein (p.Arg450His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the TSHR protein (p.Arg450His). This variant is present in population databases (rs189261858, gnomAD 0.3%). This missense change has been observed in individual(s) with autosomal recessive congenital hypothyroidism (PMID: 11442002, 19506388, 21677043, 30083029, 31356790). 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: 225505). 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: 11442002, 16756469, 21677043, 30083029). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001961453.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Dec 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypothyroidism due to TSH receptor mutations (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175669.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023
Likely pathogenic (Apr 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238775.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Apr 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329921.8 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies of transfected COS-7 cells showed slightly decreased cAMP production and a slightly decreased binding to thyroid stimulating hormone (Nagashima et al., 2001); … (more) Published functional studies of transfected COS-7 cells showed slightly decreased cAMP production and a slightly decreased binding to thyroid stimulating hormone (Nagashima et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22405933, 30083029, 28444304, 21677043, 29650690, 22876533, 21714469, 11442002, 15693879, 19158199, 27637299, 27084275, 29092890, 26990548, 28455095, 30022773, 31356790, 21707688, 29973617, 30577886, 32425884, 34248839, 23926367, 31589614, 32319661, 32459320) (less)

Comment:

Across a selection of the available literature, the TSHR c.1349G>A (p.Arg450His) missense variant has been identified in a homozygous state in at least ten individuals with congenital hypothyroidism, in a compound heterozygous state in at least four patients, and in a heterozygous state in ten patients in whom a second variant was not identified (Shibayama et al. 2005; Mizuno et al. 2009; Lee et al. 2011; Narumi et al. 2011; Chang et al. 2012; Fu et al. 2016). In at least one family, unaffected parents were identified as heterozygous carriers of the p.Arg450His variant. This variant was absent from 300 control chromosomes, but is reported at a frequency of 0.00335 in the East Asian population from the Exome Aggregation Consortium. In COS-7 cells, the p.Arg450His variant demonstrated slightly decreased cAMP production and slightly decreased TSH binding compared to wild type (Nagashima et al. 2001). In HEK293 cells, the p.Arg450His variant demonstrated 42% activity for Gs-coupled signaling and 8% activity for Gq-coupled signaling compared to wildtype (Narumi et al. 2011). Based on the collective evidence, the p.Arg450His 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.

Comment:

The p.Arg450His variant in TSHR has been reported in the homozygous or compound heterozygous state in >20 individuals with congenital hypothyroidism (Nagashima 2001, Shibayama 2005, Kanda 2006, Narumi 2009, Mizuno 2009, Satoh 2009, Ma 2010, Lee 2011, Narumi 2011, Chang 2012, Tsunekawa 2014, Park 2016, Wang 2017). Heter ozygous family members frequently displayed subclinical hypothyroidism (Ma 2010, Narumi 2009, Kanda 2006, Nagashima 2001). A significant association between the p.Arg450His variant and the risk of congenital hypothyroidism has been observed in one study (Chang 2012). This variant has been identified in 0.26% (49/18868) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs189261858). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. In vitro functional studies provide some evidence that the p.Arg450H is variant may impact protein function (Nagashima 2001, Narumi 2009, Narumi 2011 ); however, these types of assays may not accurately represent biological functi on. Computational prediction tools and conservation analysis suggest that the p. Arg450His variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, this variant meets our criter ia to be classified as pathogenic for congenital hypothyroidism in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PP3; PS3_Supporting .

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the TSHR protein (p.Arg450His). This variant is present in population databases (rs189261858, gnomAD 0.3%). This missense change has been observed in individual(s) with autosomal recessive congenital hypothyroidism (PMID: 11442002, 19506388, 21677043, 30083029, 31356790). 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: 225505). 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: 11442002, 16756469, 21677043, 30083029). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies of transfected COS-7 cells showed slightly decreased cAMP production and a slightly decreased binding to thyroid stimulating hormone (Nagashima et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22405933, 30083029, 28444304, 21677043, 29650690, 22876533, 21714469, 11442002, 15693879, 19158199, 27637299, 27084275, 29092890, 26990548, 28455095, 30022773, 31356790, 21707688, 29973617, 30577886, 32425884, 34248839, 23926367, 31589614, 32319661, 32459320)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism.	Fang Y	Clinica chimica acta; international journal of clinical chemistry	2019	PMID: 31356790
Identification of compound heterozygous TSHR mutations (R109Q and R450H) in a patient with nonclassic TSH resistance and functional characterization of the mutant receptors.	Sugisawa C	Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology	2018	PMID: 30083029
Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis.	Wang F	Clinica chimica acta; international journal of clinical chemistry	2017	PMID: 28455095
A frequent oligogenic involvement in congenital hypothyroidism.	de Filippis T	Human molecular genetics	2017	PMID: 28444304
Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients.	Fu C	Clinica chimica acta; international journal of clinical chemistry	2016	PMID: 27637299
Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer.	Hart SN	BMJ open	2016	PMID: 27084275
DUOX2 Mutations Are Frequently Associated With Congenital Hypothyroidism in the Korean Population.	Park KJ	Annals of laboratory medicine	2016	PMID: 26709262
Frequency and clinical implication of the R450H mutation in the thyrotropin receptor gene in the Japanese population detected by Smart Amplification Process 2.	Tsunekawa K	BioMed research international	2014	PMID: 24895636
TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis.	Cangul H	Journal of pediatric endocrinology & metabolism : JPEM	2012	PMID: 22876533
R450H TSH receptor mutation in congenital hypothyroidism in Taiwanese children.	Chang WC	Clinica chimica acta; international journal of clinical chemistry	2012	PMID: 22405933
Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism.	Lee ST	Clinical endocrinology	2011	PMID: 21707688
Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake.	Narumi S	The Journal of clinical endocrinology and metabolism	2011	PMID: 21677043
The R450H mutation and D727E polymorphism of the thyrotropin receptor gene in a Chinese child with congenital hypothyroidism.	Ma SG	Journal of pediatric endocrinology & metabolism : JPEM	2010	PMID: 21714469
Genetic analysis in children with transient thyroid dysfunction or subclinical hypothyroidism detected on neonatal screening.	Satoh M	Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology	2009	PMID: 23926367
Longitudinal evaluation of patients with a homozygous R450H mutation of the TSH receptor gene.	Mizuno H	Hormone research	2009	PMID: 19506388
TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study.	Narumi S	The Journal of clinical endocrinology and metabolism	2009	PMID: 19158199
Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese.	Kanda K	Endocrine	2006	PMID: 17526952
Identification and functional analysis of novel inactivating thyrotropin receptor mutations in patients with thyrotropin resistance.	Tsunekawa K	Thyroid : official journal of the American Thyroid Association	2006	PMID: 16756469
Subclinical hypothyroidism caused by a mutation of the thyrotropin receptor gene.	Shibayama K	Pediatrics international : official journal of the Japan Pediatric Society	2005	PMID: 15693879
Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin.	Nagashima T	Thyroid : official journal of the American Thyroid Association	2001	PMID: 11442002
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Text-mined citations for rs189261858 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000369.5(TSHR):c.1349G>A (p.Arg450His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs189261858 ...