NM_000369.5(TSHR):c.1556G>A (p.Arg519His) AND Hypothyroidism due to TSH receptor mutations

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Mar 17, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001118351.8

Allele description [Variation Report for NM_000369.5(TSHR):c.1556G>A (p.Arg519His)]

NM_000369.5(TSHR):c.1556G>A (p.Arg519His)

Genes:

TSHR-AS1:TSHR antisense RNA 1 [Gene - HGNC]
TSHR:thyroid stimulating hormone receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.1

Genomic location:

Preferred name:

NM_000369.5(TSHR):c.1556G>A (p.Arg519His)

HGVS:

NC_000014.9:g.81143614G>A
NG_009206.1:g.193090G>A
NM_000369.5:c.1556G>AMANE SELECT
NP_000360.2:p.Arg519His
LRG_523t1:c.1556G>A
LRG_523:g.193090G>A
NC_000014.8:g.81609958G>A
NM_000369.2:c.1556G>A

Protein change:

R519H

Links:

dbSNP: rs780018604

NCBI 1000 Genomes Browser:

rs780018604

Molecular consequence:

NM_000369.5:c.1556G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypothyroidism due to TSH receptor mutations
Synonyms:: HYPOTHYROIDISM DUE TO UNRESPONSIVENESS TO THYROTROPIN; HYPOTHYROIDISM, CONGENITAL, DUE TO TSH RESISTANCE; HYPOTHYROIDISM, NONAUTOIMMUNE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010142; MedGen: C3493776; Orphanet: 90673; OMIM: 275200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001276624	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10870027, 21586576 Citation Link,
SCV004804790	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 17, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001276624

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004804790

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 17, 2024)

germline

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

The human thyrotropin receptor is highly mutable: a review of gain-of-function mutations.

Farid NR, Kascur V, Balazs C.

Eur J Endocrinol. 2000 Jul;143(1):25-30. Review.

PubMed [citation]

PMID:: 10870027

From molecular details of the interplay between transmembrane helices of the thyrotropin receptor to general aspects of signal transduction in family a G-protein-coupled receptors (GPCRs).

Kleinau G, Hoyer I, Kreuchwig A, Haas AK, Rutz C, Furkert J, Worth CL, Krause G, Schülein R.

J Biol Chem. 2011 Jul 22;286(29):25859-71. doi: 10.1074/jbc.M110.196980. Epub 2011 May 17.

PubMed [citation]

PMID:: 21586576
PMCID:: PMC3138303

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001276624.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004804790.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 1, 2025

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