chr3-24127623-C-G

Variant names:

• chr3-24127623-C-G
• rs121918688
• NM_001354712.2:c.1020G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001354712.2(THRB):​c.1020G>C​(p.Gln340His) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q340L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.77
• Publications: 4 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 11 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001354712.2
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.975
• PP5: Variant 3-24127623-C-G is Pathogenic according to our data. Variant chr3-24127623-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12536.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.1020G>C	p.Gln340His	missense_variant	Exon 10 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.1020G>C	p.Gln340His	missense_variant	Exon 10 of 11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2

May 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 04, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: THRB c.1020G>C (p.Gln340His) results in a non-conservative amino acid change located in the Nuclear receptor ligand-binding domain (IPR035500) 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 251472 control chromosomes. c.1020G>C has been reported in the literature in multiple heterozygous individuals affected with Generalized Thyroid Hormone Resistance from one family showing segregation with disease and autosomal dominant inheritance (e.g. Usala_1991). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 1846005). ClinVar contains an entry for this variant (Variation ID: 12536). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	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		2.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.026	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Benign	0.067	T;T;.;.;.;.;.;.;T;.;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.92
MutPred		0.92		Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);.;
MVP		0.93
MPC		1.7
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.79
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121918688; hg19: chr3-24169114;