VCV001705477.2 - ClinVar

NM_001354712.2(THRB):c.1354C>T (p.Pro452Ser)

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.

(2)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001354712.2(THRB):c.1354C>T (p.Pro452Ser)

Variation ID: 1705477 Accession: VCV001705477.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.2 3: 24122916 (GRCh38) [ NCBI UCSC ] 3: 24164407 (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	Sep 17, 2022	Mar 30, 2024	Jan 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001354712.2:c.1354C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001341641.1:p.Pro452Ser	missense
NM_000461.5:c.1354C>T	NP_000452.2:p.Pro452Ser	missense
NM_001128176.3:c.1354C>T	NP_001121648.1:p.Pro452Ser	missense
NM_001128177.2:c.1354C>T	NP_001121649.1:p.Pro452Ser	missense
NM_001252634.2:c.1354C>T	NP_001239563.1:p.Pro452Ser	missense
NM_001354708.2:c.1354C>T	NP_001341637.1:p.Pro452Ser	missense
NM_001354709.2:c.1354C>T	NP_001341638.1:p.Pro452Ser	missense
NM_001354710.2:c.1354C>T	NP_001341639.1:p.Pro452Ser	missense
NM_001354711.2:c.1354C>T	NP_001341640.1:p.Pro452Ser	missense
NM_001354713.2:c.1354C>T	NP_001341642.1:p.Pro452Ser	missense
NM_001354714.2:c.1261C>T	NP_001341643.1:p.Pro421Ser	missense
NM_001354715.2:c.1261C>T	NP_001341644.1:p.Pro421Ser	missense
NM_001374822.1:c.1354C>T	NP_001361751.1:p.Pro452Ser	missense
NM_001374823.1:c.1354C>T	NP_001361752.1:p.Pro452Ser	missense
NM_001374824.1:c.1354C>T	NP_001361753.1:p.Pro452Ser	missense
NM_001374825.1:c.1354C>T	NP_001361754.1:p.Pro452Ser	missense
NM_001374826.1:c.1354C>T	NP_001361755.1:p.Pro452Ser	missense
NM_001374827.1:c.1183C>T	NP_001361756.1:p.Pro395Ser	missense
NC_000003.12:g.24122916G>A
NC_000003.11:g.24164407G>A
NG_009159.1:g.376907C>T

... more HGVS ... less HGVS

Protein change

P395S, P421S, P452S

Other names

Canonical SPDI

NC_000003.12:24122915:G:A

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

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	323	367

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	Likely pathogenic (1)	criteria provided, single submitter	Sep 1, 2022	RCV002283791.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 23, 2024	RCV003987991.1

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.
Likely pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thyroid hormone resistance, generalized, autosomal dominant Affected status: yes Allele origin: germline	3billion Accession: SCV002572878.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (3) PubMed: 29262478‚ 24722129‚ 27168936 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with THRB-related disorder (PMID: 29262478). Different missense changes at the same codon (p.Pro452Arg, p.Pro452Leu) have been reported to be associated with THRB-related disorder (PMID: 24722129 , 27168936). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Constipation (present) , Congenital hypothyroidism (present)
Uncertain significance (Jan 23, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803680.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 29262478 Comment: Variant summary: THRB c.1354C>T (p.Pro452Ser) 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.1354C>T (p.Pro452Ser) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1354C>T has been reported in the literature in at least one individual affected with Thyroid Hormone Resistance (Sun_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29262478). ClinVar contains an entry for this variant (Variation ID: 1705477). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with THRB-related disorder (PMID: 29262478). Different missense changes at the same codon (p.Pro452Arg, p.Pro452Leu) have been reported to be associated with THRB-related disorder (PMID: 24722129 , 27168936). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Variant summary: THRB c.1354C>T (p.Pro452Ser) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1354C>T has been reported in the literature in at least one individual affected with Thyroid Hormone Resistance (Sun_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29262478). ClinVar contains an entry for this variant (Variation ID: 1705477). Based on the evidence outlined above, the variant was classified as uncertain significance.

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
[Clinical characteristics of thyroid hormone resistance syndrome in two cases with different subtypes].	Sun H	Zhonghua er ke za zhi = Chinese journal of pediatrics	2017	PMID: 29262478
Coexistence of resistance to thyroid hormone and papillary thyroid carcinoma.	Igata M	Endocrinology, diabetes & metabolism case reports	2016	PMID: 27168936
Identification of four novel mutations in the thyroid hormone receptor-β gene in 164 Spanish and 2 Greek patients with resistance to thyroid hormone.	Amor AJ	Hormones (Athens, Greece)	2014	PMID: 24722129

Text-mined citations for this variant ...

Record last updated Mar 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001354712.2(THRB):c.1354C>T (p.Pro452Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...