chr14-81062179-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2

The NM_000369.5(TSHR):c.202C>T(p.Pro68Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000359 in 1,611,868 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 2 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:7

Conservation

PhyloP100: 4.69

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 Likely_benign. Variant got -5 ACMG points.

PP5

Variant 14-81062179-C-T is Pathogenic according to our data. Variant chr14-81062179-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437071.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=2, Likely_pathogenic=3}. Variant chr14-81062179-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.23717248). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000366 (534/1459658) while in subpopulation MID AF= 0.00435 (25/5750). AF 95% confidence interval is 0.00302. There are 2 homozygotes in gnomad4_exome. There are 294 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.202C>T	p.Pro68Ser	missense_variant	Exon 2 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.202C>T	p.Pro68Ser	missense_variant	Exon 2 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000543

AC:

136

AN:

250508

Hom.:

AF XY:

0.000635

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000668

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000459

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000366

AC:

534

AN:

1459658

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

294

AN XY:

726136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.000717

Gnomad4 ASJ exome

AF:

0.00265

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.000531

GnomAD4 genome

AF:

0.000296

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000440

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000584

AC:

ExAC

AF:

0.000643

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3462

EpiCase

AF:

0.00109

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Dec 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state in a patient with congenital hypothyroidism in the published literature, although this variant was inherited from a parent with unknown clinical status (PMID: 34248839); Published functional studies suggest this variant is associated with decreased TSH binding capacity and a reduction in cell-surface expression, but no overall effect on biological activity (PMID: 19820021, 19240155); Additional functional studies suggest this variant reduces TSH-stimulated downstream activity in cells transfected with P68S alone (simulating homozygosity) but no effect noted when cotransfecting P68S and wild-type TSHR (simulating heterozygosity) (PMID: 19240155); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in homozygous state in one clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 27060741, 31589614, 34248839, 34426522, 26556299, 33558524, 34200080, 26990548, 28444304, 22049173, 34308104, 36913313, 36964991, 28561265, 34780050, 39337518, 25557138, 19820021, 19240155) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSHR p.P68S variant was identified in 2 of 382 proband chromosomes (frequency: 0.0052) from individuals with non-autoimmune subclinical hypothyroidism non-autoimmune hyperthyrotropinemia (Nicoletti_2009_PMID:19820021; Calebiro_2012_PMID:22049173). In a large consanguineous family with resistance to TSH, the p.P68S variant was found in 4 family members in the heterozygous state (1 mildly affected, 3 unaffected) and in 4 family members in the compound heterozygous state (2 affected, 2 mildly affected). Functional assays showed a decrease in TSHR activity when the p.P68S TSHR variant was transfected into HEK-293 cells alone, but not when transfected as wildtype-TSHR/p.P68S (mimicking heterozygosity) (Tenenbaum-Rakover_2009_PMID:19240155). The p.P68S variant was also identified in 4 of 111 pediatric patients; 3 patients had subclinical hypothyroidism (2 heterozygous, 1 compound heterozygous) and 1 patient had congenital hypothyroidism (heterozygous) (Vigone_2017_PMID:28561265). The variant was identified in dbSNP (ID: rs142063461), ClinVar (classified as uncertain significance by Illumina and as likely pathogenic by Genetic Services Laboratory, University of Chicago) and LOVD 3.0 (classified as likely pathogenic). The variant was identified in control databases in 140 of 281886 chromosomes (1 homozygous) at a frequency of 0.0004967 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 18 of 10358 chromosomes (freq: 0.001738), South Asian in 37 of 30534 chromosomes (freq: 0.001212), Other in 5 of 7178 chromosomes (freq: 0.000697), Latino in 24 of 35272 chromosomes (freq: 0.00068), European (non-Finnish) in 55 of 128682 chromosomes (freq: 0.000427) and African in 1 of 24926 chromosomes (freq: 0.00004), but was not observed in the East Asian or European (Finnish) populations. The p.P68 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the potential impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional in vitro assays showed a decrease in cell surface expression of TSHR with the p.P68S compared to wildtype but no significant difference in biological activity (Nicoletti_2009_PMID:19820021). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with serine at codon 68 of the TSHR protein (p.Pro68Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs142063461, ExAC 0.1%). This missense change has been observed in individual(s) with clinical features of hypothyroidism (PMID: 19240155, 25557138). In at least one individual the data is consistent with the variant 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: 437071). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TSHR function (PMID: 19240155, 19820021). For these reasons, this variant has been classified as Pathogenic. -

May 01, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypothyroidism due to TSH receptor mutations

Pathogenic:1Uncertain:1

Jul 01, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSHR c.202C>T (p.Pro68Ser) variant has been reported in five studies in which it is found in at least 16 individuals affected with high TSH levels, including in five in a compound heterozygous state (two of whom were unrelated) and eleven in a heterozygous state (seven of whom were unrelated) (Tenenbaum-Rakover et al. 2009; Nicoletti et al. 2009; Calebiro et al. 2012; Deeb et al. 2016; Vignone et al. 2017). Only two of the above individuals had clinical symptoms of congenital hypothyroidism, and both individuals carried the p.Pro68Ser variant in a heterozygous state (Deeb et al. 2016; Vignone et al. 2017). The other individuals were classified as mildly affected with congenital hypothyroidism. The p.Pro68Ser variant was identified in a heterozygous state in three of 213 controls (Tenenbaum-Rakover et al. 2009; Nicoletti et al. 2009) and is reported at a frequency of 0.00332 in the Other population of the Exome Aggregation Consortium. One homozygote is reported in the South Asian population in the Genome Aggregation Database. Surface expression of the p.Pro68Ser variant was found to be reduced by 80% in HEK-293 cells and by 50% in COS-7 cells compared to wild type, but the biological activity as measured by cAMP production was not affected (Tenenbaum-Rakover et al. 2009; Nicoletti et al. 2009). Based on the collective evidence supporting a mild phenotype, the p.Pro68Ser variant is classified as a variant of unknown significance, but suspicious for pathogenicity for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Familial hyperthyroidism due to mutations in TSH receptor

Uncertain:2

Apr 21, 2023

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2022

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial gestational hyperthyroidism

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jul 27, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202C>T (p.P68S) alteration is located in exon 2 (coding exon 2) of the TSHR gene. This alteration results from a C to T substitution at nucleotide position 202, causing the proline (P) at amino acid position 68 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, this alteration is likely pathogenic for autosomal recessive congenital nongoitrous hypothyroidism; however, the association of this alteration with autosomal dominant nonautoimmune hyperthyroidism is unlikely. Based on data from the Genome Aggregation Database (gnomAD), the TSHR c.202C>T alteration was observed in 0.05% (140/281886) of total alleles studied, with a frequency of 0.17% (18/10358) in the Ashkenazi Jewish subpopulation. This variant has been observed as compound heterozygous with other TSHR variants in several individuals with elevated TSH levels and it has been reported to segregate with elevated TSH in multiple families (Tennenbaum-Rakover, 2009; Tennenbaum-Rakover, 2015; Vigone, 2017). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies show that in the homozygous and compound heterozygous states, this alteration leads to a significant reduction in TSHR activity compared to wild-type (Tennenbaum-Rakover, 2009). Based on the available evidence, this alteration is classified as likely pathogenic. -

TSHR-related disorder

Pathogenic:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSHR c.202C>T variant is predicted to result in the amino acid substitution p.Pro68Ser. This variant has been reported in the homozygous and compound heterozygous states in individuals with hyperthyrotropinemia and mild hyperthyrotropinemia, and functional studies have found that this amino acid substitution decreases substrate binding capacity of the protein (Tenenbaum-Rakover et al., 2009. PubMed ID: 19240155; Nicoletti et al. 2009. PubMed ID: 19820021; Tenenbaum-Rakover et al. 2015. PubMed ID: 25557138). This variant is reported in 0.17% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. 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

Jun 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Uncertain:1

Apr 08, 2020

Center of Medical Genetics and Primary Health Care

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

ACMG Guidelines 2015 criteria PP2 Pathogenic Supporting: 38 out of 52 non-VUS missense variants in gene TSHR are PATH = 73.1% > threshold of 51.0%, and 44 out of 118 clinically reported variants in gene TSHR are PATH = 37.3% > threshold of 12.0%. PP3 Pathogenic Supporting: 9 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and REVEL vs 2 benign predictions from PrimateAI and SIFT. PP4 Pathogenic Supporting: The variant was detected in a female patient diagnosed with breast cancer at the age of 28 y.o. However, the current data are insufficient to assess the role of the variant in the development of breast cancer. Therefore, this variant was classified as a Variant of Unknown Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;.;.;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

.;T;D;T;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.0

.;M;.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Benign

0.21

T;T;T;T;T

Sift4G

Benign

0.14

T;D;T;D;D

Polyphen

0.99

.;D;.;.;.

Vest4

0.91

MVP

1.0

MPC

0.55

ClinPred

0.47

GERP RS

5.3

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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