rs189261858

Variant names:

• chr14-81143407-G-A
• rs189261858
• NM_000369.5:c.1349G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-81143407-G-A
• chr14-81143407-G-C
• chr14-81143407-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PP2 PP3 PP5_Very_Strong BP4

The NM_000369.5(TSHR):​c.1349G>A​(p.Arg450His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 10.0
• Publications: 66 publications found

Genes affected

TSHR (HGNC:12373): (thyroid stimulating hormone receptor) The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

TSHR Gene-Disease associations (from GenCC):

• familial gestational hyperthyroidism

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• hypothyroidism due to TSH receptor mutations

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial hyperthyroidism due to mutations in TSH receptor

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284959 (HGNC:58172):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to hypothyroidism due to TSH receptor mutations, athyreosis, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.
• PP3: Multiple lines of computational evidence support a deleterious effect 11: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 14-81143407-G-A is Pathogenic according to our data. Variant chr14-81143407-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25334734). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.1349G>A	p.Arg450His	missense	Exon 10 of 10	NP_000360.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.1349G>A	p.Arg450His	missense	Exon 10 of 10	ENSP00000298171.2
	TSHR	ENST00000541158.6	TSL:5	c.1349G>A	p.Arg450His	missense	Exon 11 of 11	ENSP00000441235.2
	TSHR	ENST00000636454.1	TSL:5	n.1267G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152102 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000235 AC: 59 AN: 251452 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 163 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00272 AC: 108 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112010

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152220 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74414

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:7

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSHR c.1349G>A (p.Arg450His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251452 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TSHR causing Hypothyroidism Due To TSH Receptor Mutations, allowing no conclusion about variant significance. c.1349G>A has been reported in the literature in at-least three individuals (at a homozygous state) affected with hypothyroidism, and in at-least three individuals, at a heterozygous state, with fully or partially compensated hypothyroidism (example, Kanda_2006). 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. The most pronounced variant effect results in 8% of normal Gq activity by NFATRE-luciferase reporter assay (Narumi_2011). The following publications have been ascertained in the context of this evaluation (PMID: 17526952, 21677043). ClinVar contains an entry for this variant (Variation ID: 225505). Based on the evidence outlined above, the variant was classified as pathogenic.

Dec 13, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Aug 14, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.83 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225505 /PMID: 11442002). A different missense change at the same codon (p.Arg450Cys) has been reported to be associated with TSHR related disorder (PMID: 25557138). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Nov 29, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 176 heterozygote(s), 1 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by many clinical laboratories in ClinVar, and has been observed in a compound heterozygous or homozygous state in individuals with congenital hypothyroidism (PMID: 38433572). Additional information: Variant is predicted to result in a missense amino acid change from arginine to histidine - This variant is heterozygous; This gene is associated with both recessive and dominant disease (OMIM); Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4 highest allele count: 9 heterozygote(s), 0 homozygote(s)); Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is associated with autosomal recessive hypothyroidism, congenital, nongoitrous, 1 (MIM#275200), while gain of function is associated with autosomal dominant hyperthyroidism, familial gestational (MIM#603373), and hyperthyroidism, nonautoimmune (MIM#609152) (PMIDs: 38194289; 23154162); This variant has been shown to be paternally inherited (by trio analysis).

not provided Pathogenic:4

Feb 27, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Familial gestational hyperthyroidism Pathogenic:1

Sep 16, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting

Ovarian cancer Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial hyperthyroidism due to mutations in TSH receptor;C1863959:Familial gestational hyperthyroidism;C3493776:Hypothyroidism due to TSH receptor mutations Pathogenic:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital hypothyroidism Pathogenic:1

Jul 17, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 .

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	1.1	D
PhyloP100		10
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.78
MVP		1.0
MPC		0.74
ClinPred		0.34	T
GERP RS		5.7
gMVP		0.69
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs189261858; hg19: chr14-81609751; COSMIC: COSV99991797;