NM_000369.5:c.394G>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP2PP3PP5_Very_Strong

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 Likely pathogenic (★★).

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

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4B:1

Conservation

PhyloP100: 5.93

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

familial gestational hyperthyroidism
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
hypothyroidism due to TSH receptor mutations
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
familial hyperthyroidism due to mutations in TSH receptor
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSHR links:

TSHR-AS1 (HGNC:58172):

TSHR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to hypothyroidism due to TSH receptor mutations, athyreosis, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 14-81091070-G-C is Pathogenic according to our data. Variant chr14-81091070-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 314693.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.394G>C	p.Gly132Arg	missense_variant, splice_region_variant	Exon 5 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.394G>C	p.Gly132Arg	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

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

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

248890

AF XY:

0.0000445

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 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

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.000202

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110772

Other (OTH)

AF:

0.00

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151670

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41206

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000963

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial gestational hyperthyroidism

Pathogenic:1

Mar 26, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TSHR-related disorder

Pathogenic:1

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

Pathogenic:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jan 13, 2016

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Ovarian cancer

Benign:1

Jan 01, 2022

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

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

5.9

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

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.77

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over