chr14-81062179-C-T

Variant names:

• chr14-81062179-C-T
• rs142063461
• NM_000369.5:c.202C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:6
• Conservation: PhyloP100: 4.69

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]

ENSG00000284959 (HGNC:58172):

LOC101928462 (HGNC:):

ACMG classification

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: {Likely_pathogenic=3, Uncertain_significance=5, Pathogenic=2}. 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	c.202C>T	p.Pro68Ser	missense_variant	Exon 2 of 10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.202C>T	p.Pro68Ser	missense_variant	Exon 2 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152092 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000635 AC XY: 86 AN XY: 135410

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.: 2 Cov.: 30 AF XY: 0.000405 AC XY: 294 AN XY: 726136

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: 45 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74440

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.: 0

Bravo AF: 0.000363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000584 AC: 5

ExAC AF: 0.000643 AC: 78

Asia WGS AF: 0.00116 AC: 4 AN: 3462

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

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. -

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) -

May 01, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

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. -

Hypothyroidism due to TSH receptor mutations Pathogenic:1

Jul 01, 2016

Genetic Services Laboratory, University of Chicago

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 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	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;.;D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	.;T;D;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.0	.;M;.;.;M
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs142063461; hg19: chr14-81528523; COSMIC: COSV105878800;