rs121908866

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000369.5(TSHR):c.1637G>A(p.Trp546Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

TSHR
NM_000369.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9B:1

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 Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.

PP5

Variant 14-81143695-G-A is Pathogenic according to our data. Variant chr14-81143695-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6439.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Likely_pathogenic=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.1637G>A	p.Trp546Ter	stop_gained	10/10	ENST00000298171.7
LOC101928462	XR_001751022.2 linkuse as main transcript	n.487+21498C>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.1637G>A	p.Trp546Ter	stop_gained	10/10	1	NM_000369.5	P1
	ENST00000646052.2 linkuse as main transcript	n.510+21498C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251346

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000289

AC:

423

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000376

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000191

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2023	Published functional studies demonstrate that this variant results in a nonfunctional protein, with negligible membrane radioligand binding (Clifton-Bligh et al., 1997).; Nonsense variant in the C-terminus 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 the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 14725684, 15863666, 12629076, 9100579, 27637299, 30665703, 29625052, 34200080, 34662886, 35177841, 8954020) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2018	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). -

Hypothyroidism due to TSH receptor mutations

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2024	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. -

TSHR-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2021

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. -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.65

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

A;A

Vest4

0.95

GERP RS

4.6

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