14-81092547-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PS1_ModeratePP5_Very_StrongBP4

The NM_000369.5(TSHR):c.484C>G(p.Pro162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.64

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:

LOC101928462 (HGNC:):

LOC101928462 links:

ENSG00000284959 (HGNC:58172):

ENSG00000284959 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

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

PP5

Variant 14-81092547-C-G is Pathogenic according to our data. Variant chr14-81092547-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.39315754). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.484C>G	p.Pro162Ala	missense_variant	Exon 6 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.484C>G	p.Pro162Ala	missense_variant	Exon 6 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251382

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000220

AC:

321

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

167

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000267

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations

Pathogenic:4

Apr 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSHR c.484C>G (p.Pro162Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251382 control chromosomes (gnomAD). c.484C>G has been reported in the literature in at least two homozygous individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. Tonacchera_1996, Camilot_2005), and in multiple other homozygous, compound heterozygous, and heterozygous individuals with resistance to TSH and subclinical hypothyroidism, presenting as abnormally high TSH levels but with normal thyroid hormone levels (e.g. Sunthornthepvarakul_1995, Tonacchera_1996, De Roux_1996, Camilot_2005, Bas_2012, Tenenbaum-Rakover_2015, de Filippis_2017, Makretskaya_2018). Publications reporting experimental evidence evaluating an impact on protein function found that the variant is associated with an approximately 2-fold reduction in cell surface expression and results in a protein capable of reaching a maximal activity level similar to WT in vitro, but with a reduced sensitivity to TSH (e.g. Sunthornthepvarakul_1995, Costagliola_1999, Sriphrapradang_2011). These data indicate that the variant is likely a hypomorphic allele which manifests as elevated TSH in most cases, but has reduced penetrance and/or a milder phenotype with regards to whether individuals present clinically with hypothyroidism or have subclinical hypothyroidism. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PM3_VeryStrong+PP4 -

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 15, 2025

Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000369.5(TSHR):c.484C>G (p.Pro162Ala) variant found in homozygous state in two unrelated families from our cohort. Variant has been reported in ClinVar as Likely pathogenic (★★) and several publications also have reported the variant in CH cases (PubMed:10560953, PubMed:16060907, PubMed:12050212, PubMed:30240412) (PP5). The variant is located in a mutational hot spot without benign variation (PM1). The variant allele was found at extremely low frequency in population databases, with no homozygous occurrence (PM2). Another missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5). Patient’s phenotype or family history is highly specific for congenital hypothyroidism due to TSHR mutations (PP4). This is a missense variant in a gene in which missense variants are a common mechanism of disease (PP2). The variant c.484C>G is Pathogenic according to the ACMG guideline criteria. -

not provided

Pathogenic:4

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported heterozygous in individuals with subclinical hypothyroidism with variable expressivity (PMID: 17697008, 16060907); Published functional studies demonstrate a damaging effect on normal TSHR function (PMID: 10560953, 7528344); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7528344, 20718767, 34426522, 31589614, 22995991, 26990548, 23329763, 16060907, 12050212, 28444304, 17456567, 31287502, 30240412, 25557138, 34200080, 23154162, 34308104, 34919466, 15531543, 26229975, 28404951, 28719003, 26934580, 26659599, 31855179, 28007035, 26986070, 29691392, 27915290, 26147798, 21490078, 17697008, 26740555, 30665703, 11549705, 8954020, 10560953) -

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 162 of the TSHR protein (p.Pro162Ala). This variant is present in population databases (rs121908863, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive TSHR-related conditions (PMID: 7528344, 8954020, 16060907, 28444304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6435). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. Experimental studies have shown that this missense change affects TSHR function (PMID: 7528344, 10560953). For these reasons, this variant has been classified as Pathogenic. -

Jun 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial gestational hyperthyroidism

Pathogenic:1

Aug 09, 2022

Baylor Genetics

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 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Uncertain

0.59

.;.;.;D;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

.;D;D;D;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.39

T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.8

.;L;.;.;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.75

N;N;N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.066

T;T;T;T;T

Sift4G

Benign

0.49

T;T;T;T;T

Polyphen

0.25

.;B;.;.;.

Vest4

0.65

MVP

0.99

MPC

0.32

ClinPred

0.057

GERP RS

5.3

gMVP

0.72

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