rs121918691

chr3-24122946-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001354712.2(THRB):c.1324A>G(p.Met442Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.22

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001354712.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, THRB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 3-24122946-T-C is Pathogenic according to our data. Variant chr3-24122946-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.1324A>G	p.Met442Val	missense_variant	11/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.1324A>G	p.Met442Val	missense_variant	11/11		NM_001354712.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with resistance to thyroid hormone (RTH) (PMIDs: 1661299 (1991) and 21871106 (2011)). Functional studies report the variant is damaging to protein function (PMIDs: 1661299 (1991) and 2555064 (1989)). 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. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2023	Observed in two siblings with generalized thyroid hormone resistance (Parrilla et al., 1991); Published functional studies demonstrate a damaging effect resulting in reduction of binding affinity of the THRB receptor (Parrilla et al., 1991); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 2555064, 8013151, 19378427, 1661299, 21871106) -

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1994	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2022	Variant summary: THRB c.1324A>G (p.Met442Val) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.1324A>G has been reported in the literature in individuals affected with Thyroid Hormone Resistance, Generalized or pituitary-selective. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

THRB-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2023

The THRB c.1324A>G variant is predicted to result in the amino acid substitution p.Met442Val. This variant has been observed in multiple patients with thyroid hormone resistance (THR) (see, for example, Ono et al. 1991. PubMed ID: 1682340; Adams et al. 1994. PubMed ID: 8040303; Grace et al. 1995. PubMed ID: 8535442). Additionally, another substitution at the same amino acid (p.Met442Thr) has been shown to be causative for THR (Bayer et al. 2004. PubMed ID: 15031774; Pongjantarasatian. 2012. PubMed ID: 21795843). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Based on these observations, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N;N;.;.;.;.;.;.;N;.;N
REVEL	Pathogenic	0.70
Sift	Benign	0.17	T;T;.;.;.;.;.;.;T;.;T
Sift4G	Benign	0.089	T;T;.;.;.;.;.;.;T;.;T
Polyphen		0.54	P;P;P;P;P;P;P;P;P;P;.
Vest4		0.70
MutPred		0.88		Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);Gain of methylation at K443 (P = 0.0199);.;
MVP		0.86
MPC		1.3
ClinPred		0.69	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.88

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

Other links and lift over

dbSNP: rs121918691; hg19: chr3-24164437;