rs189261858

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PS1_ModeratePM1PM5PP3PP5_Very_StrongBP4

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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R450C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 10.0

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1

Transcript NM_000369.5 (TSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a topological_domain Cytoplasmic (size 8) in uniprot entity TSHR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000369.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-81143406-C-T is described in Lovd as [Likely_pathogenic].

PP3

Multiple lines of computational evidence support a deleterious effect 10: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, 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 [Likely_pathogenic]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.1349G>A	p.Arg450His	missense_variant	10/10	ENST00000298171.7
LOC101928462	XR_001751022.2 linkuse as main transcript	n.487+21786C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.1349G>A	p.Arg450His	missense_variant	10/10	1	NM_000369.5	P1
	ENST00000646052.2 linkuse as main transcript	n.510+21786C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000235

AC:

AN:

251452

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135894

show subpopulations

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 SAS exome

AF:

0.000131

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.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00272

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000670

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 12, 2021	- -

Hypothyroidism due to TSH receptor mutations

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 13, 2021	- -
Pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 15, 2018	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. -

Familial gestational hyperthyroidism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 16, 2022

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

Ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

Congenital hypothyroidism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2018

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.25

T;T

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.78

MVP

1.0

MPC

0.74

ClinPred

0.34

GERP RS

5.7

gMVP

0.69

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over