chr14-81143695-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000369.5(TSHR):c.1637G>A(p.Trp546*) 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 Likely pathogenic (★★).

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

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:

ENSG00000284959 (HGNC:58172):

ENSG00000284959 links:

LOC101928462 (HGNC:):

LOC101928462 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 15 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 [Likely_pathogenic]. Clinvar id is 6439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.1637G>A	p.Trp546*	stop_gained	Exon 10 of 10	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 link	c.1637G>A	p.Trp546*	stop_gained	Exon 10 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant results in a nonfunctional protein, with negligible membrane radioligand binding (PMID: 9100579); Nonsense variant 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 HGMD; This variant is associated with the following publications: (PMID: 14725684, 15863666, 12629076, 27637299, 30665703, 34308104, 29625052, 34200080, 34662886, 35177841, 36451132, 8954020, 9100579) -

Sep 10, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Mar 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 13, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypothyroidism due to TSH receptor mutations

Pathogenic:3

Mar 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 18, 2024

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.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. -

Inborn genetic diseases

Pathogenic:1

Jan 26, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TSHR-related disorder

Pathogenic:1

Feb 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Pathogenic:1

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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