3-24127694-C-T

Position:

• chr3-24127694-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001354712.2(THRB):​c.949G>A​(p.Ala317Thr) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.91

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 12 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, 0.817
• PP5: Variant 3-24127694-C-T is Pathogenic according to our data. Variant chr3-24127694-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12542.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.949G>A	p.Ala317Thr	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	c.949G>A	p.Ala317Thr	missense_variant	10/11		NM_001354712.2	ENSP00000496686

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 06, 2023	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), 9459636 (1997), 10710882 (2000), 19227423 (2008), 25063548 (2014), 25040256 (2014), and 27537566 (2016)). Additionally, the variant has been reported to segregate with resistance to thyroid hormone in several families (PMIDs: 1661299 (1991), 25063548 (2014), and 27537566 (2016)). Studies assessing the variant's impact on protein function suggest a damaging effect (PMIDs: 1661299 (1991), 12554782 (2003), and 25040256 (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. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	Published functional studies demonstrate a damaging effect, as in vitro translational studies showed impaired binding affinity compared to the wild-type (Parrilla et al., 1991; Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19227423, 9459636, 17610520, 8514853, 22460197, 25063548, 25040256, 10710882, 20940675, 1661299, 30976996, 19268523, 7616549, 8013151, 2879243, 1400869, 27537566, 27535533) -

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jul 23, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2024	Variant summary: THRB c.949G>A (p.Ala317Thr) results in a non-conservative amino acid change located in the nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251452 control chromosomes (gnomAD). c.949G>A has been reported in the literature in multiple individuals affected with Autosomal Dominant, Generalized Thyroid Hormone Resistance (e.g. Parrilla_1991, Poyrazolu_2008, Macchia_2014, Guo_2016). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and found that the variant has impaired T3 binding affinity, approximately 20% that of the WT receptor (Parrilla_1991, Macchia_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27537566, 25040256, 1661299, 19227423). ClinVar contains an entry for this variant (Variation ID: 12542). 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

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (A single family has been reported for the autosomal recessive disease. Carriers of exon 4-10 deletion were clinically normal; PMID: 1991834) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 8381821). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. (p.(Ala317Val) identified in 2 unrelated patients with RTH syndrome; PMID: 24969835, 30027432) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. (ClinVar, PMID: 8040303, 8514853, 7677297) (P) 0903 - Low evidence for segregation with disease. (PMID: 7616549, 17610520) (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	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	0.83	D
PROVEAN	Benign	-1.9	N;N;.;.;.;.;.;.;N;.;N
REVEL	Pathogenic	0.78
Sift	Benign	0.077	T;T;.;.;.;.;.;.;T;.;T
Sift4G	Benign	0.56	T;T;.;.;.;.;.;.;T;.;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.93
MutPred		0.65		Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);Gain of glycosylation at S314 (P = 0.1061);.;
MVP		0.83
MPC		2.3
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.54
gMVP		0.97

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: rs121918690; hg19: chr3-24169185; COSMIC: COSV54982070;