3-24127684-C-T

Position:

• chr3-24127684-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001354712.2(THRB):​c.959G>A​(p.Arg320His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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: 0.0000014 (0 hom.)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 15 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, 0.986
• PP5: Variant 3-24127684-C-T is Pathogenic according to our data. Variant chr3-24127684-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12553.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.959G>A	p.Arg320His	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.959G>A	p.Arg320His	missense_variant	10/11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 27, 2022	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant was reported in multiple families who were affected with resistance to thyroid hormone (RTH), including those with a mild phenotype (PMIDs: 1314846 (1992), 23926384 (2010), and 25040256 (2014)). Functional studies have shown that this variant is associated with decreased T3 binding affinity (PMIDs: 1314846 (1992)) and 25040256 (2014)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2023	Published functional studies demonstrate a reduction in T3 binding affinity for the R320H variant (Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25040256, 8514853, 23926384, 16053391, 34860176, 36531240, 33524107) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 28, 2023	- -

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 12, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1993	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2015

- -

THRB-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The THRB c.959G>A variant is predicted to result in the amino acid substitution p.Arg320His. This variant has been reported to be causative for autosomal dominant thyroid hormone resistance (Weiss et al. 1993. PubMed ID: 8514853; Narumi et al. 2010. PubMed ID: 23926384; Macchia et al. 2014. PubMed ID: 25040256). Other substitutions at this same amino acid (p.Arg320Ser, p.Arg320Cys, and p.Arg320Leu) have also been found in patients with thyroid hormone resistance (Amor et al. 2014, PubMed ID: 24722129; Burman et al. 1992. PubMed ID: 1358935; Adams et al. 1994. PubMed ID: 8040303). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;M;M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Uncertain	0.012	D;D;.;.;.;.;.;.;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.95
MutPred		0.94		Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);.;
MVP		0.94
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918693; hg19: chr3-24169175;