chr3-24127685-G-T

Variant names:

• chr3-24127685-G-T
• rs121918696
• NM_001354712.2:c.958C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_001354712.2(THRB):​c.958C>A​(p.Arg320Ser) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0
• Publications: 15 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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 chr3-24127684-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12562.Status of the report is no_assertion_criteria_provided, 0 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, 0.973

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354712.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.958C>A	p.Arg320Ser	missense	Exon 10 of 11	NP_001341641.1
	THRB	NM_000461.5		c.958C>A	p.Arg320Ser	missense	Exon 9 of 10	NP_000452.2
	THRB	NM_001128176.3		c.958C>A	p.Arg320Ser	missense	Exon 10 of 11	NP_001121648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.958C>A	p.Arg320Ser	missense	Exon 10 of 11	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.958C>A	p.Arg320Ser	missense	Exon 10 of 11	ENSP00000348827.4
	THRB	ENST00000280696.9	TSL:5	c.1003C>A	p.Arg335Ser	missense	Exon 6 of 7	ENSP00000280696.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: THRB c.958C>A (p.Arg320Ser) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) 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 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.958C>A has been reported in the literature in at-least one individual affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (example: Armor_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Thyroid Hormone Resistance, Generalized, Autosomal Dominant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple different variants affecting the same amino acid residue is reported in association with Thyroid hormone resistance in HGMD and at-least one have been classified pathogenic in ClinVar with multiple entries (CV ID 12557). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

not provided Uncertain:1

Apr 01, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.98
Sift	Benign	0.052	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.85		Loss of glycosylation at P323 (P = 0.045)
MVP		0.90
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.98
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918696; hg19: chr3-24169176;