rs121918698

chr3-24122957-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001354712.2(THRB):c.1313G>A(p.Arg438His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R438C) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 19 ACMG points.

• PM1: In a hotspot region, there are 5 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-24122958-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 492921.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, THRB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 3-24122957-C-T is Pathogenic according to our data. Variant chr3-24122957-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12559.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.1313G>A	p.Arg438His	missense_variant	11/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.1313G>A	p.Arg438His	missense_variant	11/11		NM_001354712.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2023	Variant summary: THRB c.1313G>A (p.Arg438His) 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 251486 control chromosomes (gnomAD). c.1313G>A has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (examples: Adams_1994, Han_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26041374, 8040303). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1994	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 20, 2012	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 19, 2020

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity NOT confirmed. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11327621, 30430796, 32635414, 17610520, 25738994, 8670802, 8013151, 8514853, 34860176, 21871106, 22507269, 33524107, 8435883, 1677564, 9737363, 25063548, 3124992, 1548332, 8040316, 23926384, 8040303, 20237409, 31655060, 33868182, 11788648, 34727089, 26041374) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.4	L;L;L;L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Uncertain	0.017	D;D;.;.;.;.;.;.;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.63
MutPred		0.87		Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);Loss of stability (P = 0.1155);.;
MVP		0.89
MPC		2.1
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.86

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: rs121918698; hg19: chr3-24164448;