rs121918696

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001354712.2(THRB):c.958C>T(p.Arg320Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

THRB
NM_001354712.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 10.0

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THRB. . Gene score misZ 2.5652 (greater than the threshold 3.09). Trascript score misZ 3.708 (greater than threshold 3.09). GenCC has associacion of gene with thyroid hormone resistance, generalized, autosomal dominant, resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 3-24127685-G-A is Pathogenic according to our data. Variant chr3-24127685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRB	NM_001354712.2 linkuse as main transcript	c.958C>T	p.Arg320Cys	missense_variant	10/11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2 linkuse as main transcript	c.958C>T	p.Arg320Cys	missense_variant	10/11		NM_001354712.2	ENSP00000496686		P10828-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000896

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1993	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 20, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2024	Variant summary: THRB c.958C>T (p.Arg320Cys) 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 251466 control chromosomes (gnomAD). c.958C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant with evidence of cosegregation with disease (e.g. Burman_1992). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in substantially reduced T3 binding (Burman_1992). The following publication has been ascertained in the context of this evaluation (PMID: 1358935). ClinVar contains an entry for this variant (Variation ID: 12557). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2022	Reported in the heterozygous state (as c.1243C>T due to alternate nomenclature) in multiple individuals from unrelated families with resistance to thyroid hormone (Burman et al., 1992; Weiss et al., 1993; Jonas and Daumerie, 2014); Published functional studies demonstrate a damaging effect: modestly reduced T3 binding affinity compared to normal or wild type translation products (Burman et al., 1992); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33524107, 30430796, 21703645, 9086567, 35738449, 20237409, 30526530, 28938413, 34556608, 34727089, 30027432, 1358935, 8514853, 25099553, 26582918, 24077912) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2020	In the published literature, the variant has been reported to segregate with disease in families affected with resistance to thyroid hormone, and functional studies indicate this variant results in a hormone binding defect (PMID: 1358935 (1992), 8514853 (1993), 9086567 (1997), 21703645 (2011)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

THRB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2024

The THRB c.958C>T variant is predicted to result in the amino acid substitution p.Arg320Cys. This variant has been reported in multiple unrelated patients with thyroid hormone resistance (Burman et al. 1992. PubMed ID: 1358935; Weiss et al. 1997. PubMed ID: 9086567; Zaig et al. 2018. PubMed ID: 30430796). Experimental studies suggest this variant impacts protein function by decreasing the affinity of T3 binding (Burman et al. 1992. PubMed ID: 1358935; Lado Abeal et al. 2011. PubMed ID: 21703645). Alternate nucleotide changes affecting the same amino acid (p.Arg320Ser, p.Arg320Gly, p.Arg320His, p.Arg320Pro, p.Arg320Leu), have been reported to be disease-causing for thyroid hormone resistance (Human Gene Mutation Database). This variant has not been reported in a large population database, indicating this variant is rare. Taken together, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.2

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

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.94

Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);.;

MVP

0.97

MPC

2.8

ClinPred

1.0

GERP RS

5.8

Varity_R

0.92

gMVP

0.96

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