rs121918687

Variant names:

• chr3-24122912-G-A
• rs121918687
• NM_001354712.2:c.1358C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-24122912-G-A
• chr3-24122912-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001354712.2(THRB):​c.1358C>T​(p.Pro453Leu) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P453H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.95
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• thyroid hormone resistance, generalized, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hormone resistance, generalized, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr3-24122913-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 12550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the THRB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.5652 (below the threshold of 3.09). Trascript score misZ: 3.708 (above the threshold of 3.09). GenCC associations: The gene is linked to resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive, thyroid hormone resistance, generalized, autosomal dominant.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-24122912-G-A is Pathogenic according to our data. Variant chr3-24122912-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.1358C>T	p.Pro453Leu	missense_variant	Exon 11 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.1358C>T	p.Pro453Leu	missense_variant	Exon 11 of 11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:1

Jun 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: THRB c.1358C>T (p.Pro453Leu) results in a non-conservative amino acid change located in the 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 251490 control chromosomes (gnomAD). c.1358C>T has been reported in the literature in three individuals (two siblings and their father) affected with Thyroid Hormone Resistance and was found to segregate with the disease phenotype in this family in an autosomal dominant pattern (Rivolta_2009, Chiesa_2012). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant had a reduced affinity for T3 and resulted in a decreased induction of expression from T3 response elements compared to the WT protein (Zavacki_1993). Additionally, several variants affecting the same amino acid (Pro453Ser, Pro453Thr, Pro453Ala) have been classified as pathogenic, suggesting Pro453 is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21870171, 19268523, 8264663). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;M;M;.
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;.;.;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.71
MutPred		0.91		Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);.;
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.98
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs121918687; hg19: chr3-24164403; COSMIC: COSV54979728;