3-24133398-G-C

Variant names:

• chr3-24133398-G-C
• rs750905761
• NM_001354712.2:c.803C>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001354712.2(THRB):​c.803C>G​(p.Ala268Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 13 ACMG points.

• 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 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, 0.924
• PP5: Variant 3-24133398-G-C is Pathogenic according to our data. Variant chr3-24133398-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.803C>G	p.Ala268Gly	missense_variant	Exon 9 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.803C>G	p.Ala268Gly	missense_variant	Exon 9 of 11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The THRB c.803C>G (p.Ala268Gly) variant has been reported in the published literature in individuals/families with clinical features of resistance to thyroid hormone (RTH) syndrome (PMID: 24393243 (2014), 19268523 (2009), 8956060 (1996)), and is observed to be statistically associated with disease in one family (PMID: 8956060 (1996)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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. -

Sep 01, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24393243, 19268523, 8956060, 30976996) -

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2

Feb 21, 2012

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 12, 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.803C>G (p.Ala268Gly) results in a non-conservative amino acid change in 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 251360 control chromosomes. c.803C>G has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (example, ElShafie_2014, Rivolta_2009). Particularly, this variant has been reported to co-segregate with disease in 11 affected cases and not present in the unaffected individuals of a large family diagnosed with autosomal dominant Thyroid Hormone Resistance, as a communication that has not provided enough clinical/genetic details (Jezequel_1996). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24393243, 8956060, 19268523). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Thyroid hormone resistance syndrome Pathogenic:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with thyroid hormone resistance (OMIM). 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant disease is due to the THRB mutant protein exerting a dominant negative effect on the wild type protein while recessive disease is due to a full deletion of a single THRB allele where a protein is not produced (PMID: 30976996). (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical variability and heterogeneity is well documented in affected individuals (PMID: 30976996). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Ala268Asp) variant has been identified in three individuals with resistance to thyroid hormone (PMIDs: 9707435, 27853072). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as heterozygous in four individuals with clinically confirmed resistance to thyroid hormone (PMIDs: 8956060, 19268523, 20237409, 24393243). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

THRB-related disorder Pathogenic:1

May 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The THRB c.803C>G variant is predicted to result in the amino acid substitution p.Ala268Gly. This variant has been reported in multiple patients and families with thyroid resistance (Jézéquel et al. 1996. PubMed ID: 8956060; El Shafie et al. 2014. PubMed ID: 24393243; Rivolta et al. 2009. PubMed ID: 19268523). It has not been reported in a large population database (http://gnomad.broadinstitute.org/), indicating that it is rare. Taken together, we interpret this variant as likely pathogenic. -

Thyroid hormone resistance, generalized, autosomal recessive Pathogenic:1

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;L;L;L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.85
Sift	Benign	0.041	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Benign	0.38	T;T;.;.;.;.;.;.;T;.;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.77
MutPred		0.77		Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);Loss of stability (P = 0.0394);.;
MVP		0.91
MPC		1.9
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.89

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: rs750905761; hg19: chr3-24174889;