rs121918697

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001354712.2(THRB):c.1012C>T(p.Arg338Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R338Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THRB
NM_001354712.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.23

Publications

29 publications found

Variant links:

Genes affected

THRB (HGNC:11799): (thyroid hormone receptor beta) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]

THRB Gene-Disease associations (from GenCC):

thyroid hormone resistance, generalized, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hormone resistance, generalized, autosomal recessive
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

THRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001354712.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the THRB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.5652 (below the threshold of 3.09). Trascript score misZ: 3.708 (above the threshold of 3.09). GenCC associations: The gene is linked to resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive, thyroid hormone resistance, generalized, autosomal dominant.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 3-24127631-G-A is Pathogenic according to our data. Variant chr3-24127631-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12558.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
THRB	NM_001354712.2 link	c.1012C>T	p.Arg338Trp	missense_variant	Exon 10 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2 link	c.1012C>T	p.Arg338Trp	missense_variant	Exon 10 of 11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000548

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant

Pathogenic:4

Jun 25, 2013

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 25, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: THRB c.1012C>T (p.Arg338Trp) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). c.1012C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance and was shown to segregate with disease within families (e.g. Weiss_1993, Alberobello_2011, Macchia_2014, Arsov_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Sasaki_1995, Ando_1996, Wan_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 01, 2022

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, the variant has been reported in individuals affected with selective pituitary resistance to thyroid hormone (PRTH) (PMIDs: 8514853 (1993), 8384535 (1993), 8889584 (1996), 8040303 (1994), 11518118 (2001), 16804041 (2006), 25040256 (2014), 26041374 (2015), and 30430796 (2018)). This variant is located within a hotspot in the hormone-binding domain of THRB and results in significant reduction of its T3-binding activity (PMIDs: 8674808 (1995), 8384535 (1993), 25040256 (2014), and 24174637 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging.

Selective pituitary resistance to thyroid hormone;C2937288:Thyroid hormone resistance, generalized, autosomal dominant;C3489796:Thyroid hormone resistance, generalized, autosomal recessive

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).

Selective pituitary resistance to thyroid hormone

Pathogenic:1

Sep 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;M;M;M;M;M;M;M;M;.

PhyloP100

4.2

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.6

D;D;.;.;.;.;.;.;D;.;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;.;.;.;.;.;.;D;.;D

Sift4G

Uncertain

0.0030

D;D;.;.;.;.;.;.;D;.;D

Vest4

0.93

ClinPred

1.0

GERP RS

5.0

Varity_R

0.93

gMVP

0.95

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over