VCV000012542.14 - ClinVar

NM_001354712.2(THRB):c.949G>A (p.Ala317Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001354712.2(THRB):c.949G>A (p.Ala317Thr)

Variation ID: 12542 Accession: VCV000012542.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.2 3: 24127694 (GRCh38) [ NCBI UCSC ] 3: 24169185 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 24, 2024	Feb 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001354712.2:c.949G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001341641.1:p.Ala317Thr	missense
NM_000461.5:c.949G>A	NP_000452.2:p.Ala317Thr	missense
NM_001128176.3:c.949G>A	NP_001121648.1:p.Ala317Thr	missense
NM_001128177.1:c.949G>A
NM_001128177.2:c.949G>A	NP_001121649.1:p.Ala317Thr	missense
NM_001252634.2:c.949G>A	NP_001239563.1:p.Ala317Thr	missense
NM_001354708.2:c.949G>A	NP_001341637.1:p.Ala317Thr	missense
NM_001354709.2:c.949G>A	NP_001341638.1:p.Ala317Thr	missense
NM_001354710.2:c.949G>A	NP_001341639.1:p.Ala317Thr	missense
NM_001354711.2:c.949G>A	NP_001341640.1:p.Ala317Thr	missense
NM_001354713.2:c.949G>A	NP_001341642.1:p.Ala317Thr	missense
NM_001354714.2:c.856G>A	NP_001341643.1:p.Ala286Thr	missense
NM_001354715.2:c.856G>A	NP_001341644.1:p.Ala286Thr	missense
NC_000003.12:g.24127694C>T
NC_000003.11:g.24169185C>T
NG_009159.1:g.372129G>A
	P10828:p.Ala317Thr

... more HGVS ... less HGVS

Protein change

A317T, A286T

Other names

Canonical SPDI

NC_000003.12:24127693:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA122467 UniProtKB: P10828#VAR_004635 OMIM: 190160.0006 dbSNP: rs121918690 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
THRB		-	-	GRCh38 GRCh37	325	369

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Thyroid hormone resistance, generalized, autosomal dominant	Pathogenic (3)	criteria provided, single submitter	Feb 8, 2024	RCV000013369.26
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 5, 2023	RCV000760096.13
Thyroid hormone resistance syndrome	Pathogenic (1)	criteria provided, single submitter	May 21, 2020	RCV004786256.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 05, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001783347.2 First in ClinVar: Aug 14, 2021 Last updated: May 13, 2023	Comment: Published functional studies demonstrate a damaging effect, as in vitro translational studies showed impaired binding affinity compared to the wild-type (Parrilla et al., 1991; Macchia … (more) Published functional studies demonstrate a damaging effect, as in vitro translational studies showed impaired binding affinity compared to the wild-type (Parrilla et al., 1991; Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19227423, 9459636, 17610520, 8514853, 22460197, 25063548, 25040256, 10710882, 20940675, 1661299, 30976996, 19268523, 7616549, 8013151, 2879243, 1400869, 27537566, 27535533) (less)
Pathogenic (Feb 06, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889876.3 First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024	Publications: PubMed (9) PubMed: 9459636‚ 10710882‚ 19227423‚ 27537566‚ 12554782‚ 1661299‚ 25063548‚ 20940675‚ 25040256 Comment: This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with resistance … (more) This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with resistance to thyroid hormone (RTH) (PMIDs: 1661299 (1991), 9459636 (1997), 10710882 (2000), 19227423 (2008), 25063548 (2014), 25040256 (2014), and 27537566 (2016)). Additionally, the variant has been reported to segregate with resistance to thyroid hormone in several families (PMIDs: 1661299 (1991), 25063548 (2014), and 27537566 (2016)). Studies assessing the variant's impact on protein function suggest a damaging effect (PMIDs: 1661299 (1991), 12554782 (2003), and 25040256 (2014). 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. (less)
Pathogenic (Apr 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018968.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 08, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Thyroid hormone resistance, generalized, autosomal dominant Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004813604.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (4) PubMed: 25040256‚ 1661299‚ 27537566‚ 19227423 Comment: Variant summary: THRB c.949G>A (p.Ala317Thr) results in a non-conservative amino acid change located in the nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein … (more) Variant summary: THRB c.949G>A (p.Ala317Thr) 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 251452 control chromosomes (gnomAD). c.949G>A has been reported in the literature in multiple individuals affected with Autosomal Dominant, Generalized Thyroid Hormone Resistance (e.g. Parrilla_1991, Poyrazolu_2008, Macchia_2014, Guo_2016). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and found that the variant has impaired T3 binding affinity, approximately 20% that of the WT receptor (Parrilla_1991, Macchia_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27537566, 25040256, 1661299, 19227423). ClinVar contains an entry for this variant (Variation ID: 12542). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198790.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thyroid hormone resistance syndrome Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399184.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (9) PubMed: 1991834‚ 7616549‚ 7677297‚ 8040303‚ 8381821‚ 8514853‚ 17610520‚ 24969835‚ 30027432 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (A single family has been reported for the autosomal recessive disease. Carriers of exon 4-10 deletion were clinically normal; PMID: 1991834) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 8381821). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. (p.(Ala317Val) identified in 2 unrelated patients with RTH syndrome; PMID: 24969835, 30027432) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. (ClinVar, PMID: 8040303, 8514853, 7677297) (P) 0903 - Low evidence for segregation with disease. (PMID: 7616549, 17610520) (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Pathogenic (May 01, 1995)	no assertion criteria provided Method: literature only	THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033616.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 17, 2021	Publications: PubMed (6) PubMed: 1661299‚ 2879243‚ 8013151‚ 8514853‚ 7616549‚ 1400869 Comment on evidence: In a patient with a sporadic form of GRTH (GRTHD; 188570), Parrilla et al. (1991) identified a G-to-A transition at nucleotide 1234 in exon 9 … (more) In a patient with a sporadic form of GRTH (GRTHD; 188570), Parrilla et al. (1991) identified a G-to-A transition at nucleotide 1234 in exon 9 of the THRB gene, resulting in an ala312-to-thr mutation (ALA312THR). Parrilla et al. (1991) used the nucleotide and codon numbering as originally described by Weinberger et al. (1986). This mutation is designated ala317-to thr (A317T) according the revised numbering system of Beck-Peccoz et al. (1994). In 2 unrelated families and an unrelated individual with GRTHD, Weiss et al. (1993) identified heterozygosity for the A317T mutation in the THRB gene. In a father and 2 of his children with goiter and raised thyroid hormone levels, Pohlenz et al. (1995) identified heterozygosity for the A317T mutation. They commented on the fact that 'significant articulation problems' were present in the patient studied by Parrilla et al. (1991). Mixson et al. (1992) found that more language abnormalities were thought to occur in kindreds with mutations in exon 9 than in those with mutations in exon 10. However, no abnormalities in language development, articulation problems, or signs consistent with dyslexia were found in the 3 affected members of the kindred they studied. (less)
Pathogenic (Jul 23, 2013)	no assertion criteria provided Method: clinical testing	Thyroid hormone resistance, generalized, autosomal dominant Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000692416.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018

Comment:

Published functional studies demonstrate a damaging effect, as in vitro translational studies showed impaired binding affinity compared to the wild-type (Parrilla et al., 1991; Macchia et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19227423, 9459636, 17610520, 8514853, 22460197, 25063548, 25040256, 10710882, 20940675, 1661299, 30976996, 19268523, 7616549, 8013151, 2879243, 1400869, 27537566, 27535533)

Comment:

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with resistance to thyroid hormone (RTH) (PMIDs: 1661299 (1991), 9459636 (1997), 10710882 (2000), 19227423 (2008), 25063548 (2014), 25040256 (2014), and 27537566 (2016)). Additionally, the variant has been reported to segregate with resistance to thyroid hormone in several families (PMIDs: 1661299 (1991), 25063548 (2014), and 27537566 (2016)). Studies assessing the variant's impact on protein function suggest a damaging effect (PMIDs: 1661299 (1991), 12554782 (2003), and 25040256 (2014). 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.

Comment:

Variant summary: THRB c.949G>A (p.Ala317Thr) 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 251452 control chromosomes (gnomAD). c.949G>A has been reported in the literature in multiple individuals affected with Autosomal Dominant, Generalized Thyroid Hormone Resistance (e.g. Parrilla_1991, Poyrazolu_2008, Macchia_2014, Guo_2016). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and found that the variant has impaired T3 binding affinity, approximately 20% that of the WT receptor (Parrilla_1991, Macchia_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27537566, 25040256, 1661299, 19227423). ClinVar contains an entry for this variant (Variation ID: 12542). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (A single family has been reported for the autosomal recessive disease. Carriers of exon 4-10 deletion were clinically normal; PMID: 1991834) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 8381821). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. (p.(Ala317Val) identified in 2 unrelated patients with RTH syndrome; PMID: 24969835, 30027432) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. (ClinVar, PMID: 8040303, 8514853, 7677297) (P) 0903 - Low evidence for segregation with disease. (PMID: 7616549, 17610520) (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Assessing the clinical and molecular diagnosis of inherited forms of impaired sensitivity to thyroid hormone from a single tertiary center.	Ramos LS	Endocrine	2018	PMID: 30027432
Thyroid hormone resistance syndrome caused by heterozygous A317T mutation in thyroid hormone receptor β gene: Report of one Chinese pedigree and review of the literature.	Guo QH	Medicine	2016	PMID: 27537566
Resistance to thyroid hormone due to mutations in the THRB gene impairs bone mass and affects calcium and phosphorus homeostasis.	Cardoso LF	Bone	2014	PMID: 25063548
Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor β.	Macchia E	Clinical endocrinology	2014	PMID: 25040256
Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients.	Moran C	The lancet. Diabetes & endocrinology	2014	PMID: 24969835
A mutation in thyroid hormone receptor beta causing "resistance to thyroid hormone" in a neonate.	Cömert S	Minerva pediatrica	2010	PMID: 20940675
Resistance to thyroid hormone in a Turkish child with A317T mutation in the thyroid hormone receptor-beta gene.	Poyrazoğlu S	The Turkish journal of pediatrics	2008	PMID: 19227423
Clinical features and genetic analysis of four Brazilian kindreds with resistance to thyroid hormone.	Magalhães PK	Clinical endocrinology	2007	PMID: 17610520
Two resistance to thyroid hormone mutants with impaired hormone binding.	Huber BR	Molecular endocrinology (Baltimore, Md.)	2003	PMID: 12554782
An identical neo-mutation in the thyroid hormone receptor beta gene (A317T) in 2 unrelated Thai families with resistance to thyroid hormone.	Sunthornthepvarakul T	Journal of the Medical Association of Thailand = Chotmaihet thangphaet	2000	PMID: 10710882
Mutation in the thyroid hormone receptor beta gene (A317T) in a Thai subject with resistance to thyroid hormone.	Sunthornthepvarakul T	Thyroid : official journal of the American Thyroid Association	1997	PMID: 9459636
Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study.	Brucker-Davis F	Annals of internal medicine	1995	PMID: 7677297
Phenotypic variability in patients with generalised resistance to thyroid hormone.	Pohlenz J	Journal of medical genetics	1995	PMID: 7616549
Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.	Adams M	The Journal of clinical investigation	1994	PMID: 8040303
Nomenclature of thyroid hormone receptor beta gene mutations in resistance to thyroid hormone: consensus statement from the First Workshop on Thyroid Hormone Resistance, 10-11 July 1993, Cambridge, UK.	Beck-Peccoz P	Clinical endocrinology	1994	PMID: 8013151
Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families.	Weiss RE	The Journal of clinical investigation	1993	PMID: 8514853
An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype.	Geffner ME	The Journal of clinical investigation	1993	PMID: 8381821
Correlations of language abnormalities with localization of mutations in the beta-thyroid hormone receptor in 13 kindreds with generalized resistance to thyroid hormone: identification of four new mutations.	Mixson AJ	The Journal of clinical endocrinology and metabolism	1992	PMID: 1400869
Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation.	Takeda K	The Journal of clinical investigation	1991	PMID: 1991834
Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain.	Parrilla R	The Journal of clinical investigation	1991	PMID: 1661299
The c-erb-A gene encodes a thyroid hormone receptor.	Weinberger C	Nature	1986	PMID: 2879243
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Text-mined citations for rs121918690 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001354712.2(THRB):c.949G>A (p.Ala317Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918690 ...