rs1553609185

Positions:

• chr3-24122965-A-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001354712.2(THRB):​c.1305T>G​(p.His435Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.537

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.

• 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). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. GenCC has associacion of the 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, 0.97
• PP5: Variant 3-24122965-A-C is Pathogenic according to our data. Variant chr3-24122965-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 437004.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	c.1305T>G	p.His435Gln	missense_variant	11/11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.1305T>G	p.His435Gln	missense_variant	11/11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2022	Variant summary: THRB c.1305T>G (p.His435Gln) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Several other missense variants located at this codon have been implicated in association with Thyroid hormone resistance supporting a hotspot codon essential for Thyroid hormone receptor function (Nomura_1996). Specifically, a different variant (c.1305T>A) resulting in the same alteration (p.His435Gln) has been reported in association with Thyroid hormone resistance (Tsakaguchi_1995). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes. Although specifically c.1305T>G has not been reported in the literature, the variant p.His435Gln has been reported in the literature in at-least one individual affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant and continues to be cited by others (example, Nomura_1996, Anzai_2012, Groenweg_2017, Zaig_2018, Choi_2018). At least one publication reports experimental evidence evaluating an impact of p.His435Gln on protein function (Nomura_1996). The most pronounced variant effect results in T3-binding activity below limit of detection and alters homodimer formation on certain thyroid hormone response elements (TRE) such as DR4. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Thyroid hormone resistance syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.96	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.77
Sift	Benign	0.070	T;T;.;.;.;.;.;.;T;.;T
Sift4G	Uncertain	0.0090	D;D;.;.;.;.;.;.;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.87
MutPred		0.91		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;
MVP		0.93
MPC		2.4
ClinPred		0.98	D
GERP RS		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553609185; hg19: chr3-24164456;