rs760874290

Positions:

chr14-81091070-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000369.5(TSHR):c.394G>C(p.Gly132Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000808 in 1,609,618 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TSHR
NM_000369.5 missense, splice_region

Scores

Splicing: ADA: 0.9796

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1B:2

Conservation

PhyloP100: 5.93

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.394G>C	p.Gly132Arg	missense_variant, splice_region_variant	5/10	ENST00000298171.7	NP_000360.2
LOC101928462	XR_001751022.2 linkuse as main transcript	n.881+2512C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.394G>C	p.Gly132Arg	missense_variant, splice_region_variant	5/10	1	NM_000369.5	ENSP00000298171	P1
	ENST00000646052.2 linkuse as main transcript	n.904+2512C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151670

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000402

AC:

AN:

248890

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1457948

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725494

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151670

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74018

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000963

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial gestational hyperthyroidism

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

TSHR-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a de novo compound heterozygous and homozygous change in patients with congenital nongoitrous hypothyroidism-1 (CHNG1) who exhibited increased levels of plasma TSH and low levels of thyroid hormone in infancy (PMID: 21707688, 19158199). Functional studies showed that the presence of the (p.Gly132Arg) variant resulted in reduced binding activity and impaired TSH-induced cAMP production (26% of wild type) without any significant reduction in expression level (PMID: 19158199). The c.394G>C (p.Gly132Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/280224) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.394G>C (p.Gly132Arg) variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2016

The G132R variant in the TSHR gene has been reported previously in association with congenital hypothyroidism (Lee et al., 2011; Narumi et al., 2011). And, functional characterization of the G132R variant indicates a disruption in receptor function (Narumi et al., 2009). The G132R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however, data from ethnically-matched control individuals were not available to assess for a population-specific benign variant. The G132R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The G132R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Hypothyroidism due to TSH receptor mutations

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The TSHR c.394G>C (p.Gly132Arg) missense variant has been reported in at least three studies in which it is found in a total of six patients with congenital hypothyroidism, including in one in a homozygous state, in two in a compound heterozygous state, in two in a heterozygous state, and in a heterozygous state in one patient who also carried a missense variant in another congenital hypothyroidism-associated gene (Narumi et al. 2009; Lee et al. 2011; Jin et al. 2014). The majority of these studies, however, did not screen for all the known causal genes. The p.Gly132Arg variant was absent from 100 controls, but is reported at a frequency of 0.00047 in the East Asian population of the Exome Aggregation Consortium. Functional studies in COS-7 cells showed that the p.Gly132Arg variant protein was expressed at a level comparable to that of the wild type protein but displayed severely reduced binding activity and impaired TSH-induced cAMP production (26% of wild type) (Narumi et al. 2009). The evidence for this variant is limited. The p.Gly132Arg variant is therefore classified as likley pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

.;.;.;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.68

.;N;.;.;N

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.9

N;D;N;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.082

T;D;T;D;D

Sift4G

Benign

0.098

T;T;T;T;T

Polyphen

0.95

.;P;.;.;.

Vest4

0.91

MutPred

0.74

Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);

MVP

0.98

MPC

0.44

ClinPred

0.42

GERP RS

5.8

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.050

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