VCV000006430.30 - ClinVar

NM_000369.5(TSHR):c.106G>C (p.Asp36His)

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.

(9)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000369.5(TSHR):c.106G>C (p.Asp36His)

Variation ID: 6430 Accession: VCV000006430.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q31.1 14: 80955786 (GRCh38) [ NCBI UCSC ] 14: 81422130 (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	Jun 9, 2014	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000369.5:c.106G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000360.2:p.Asp36His	missense
NM_001018036.3:c.106G>C	NP_001018046.1:p.Asp36His	missense
NM_001142626.3:c.106G>C	NP_001136098.1:p.Asp36His	missense
NC_000014.9:g.80955786G>C
NC_000014.8:g.81422130G>C
NG_009206.1:g.5262G>C
LRG_523:g.5262G>C
LRG_523t1:c.106G>C	LRG_523p1:p.Asp36His

... more HGVS ... less HGVS

Protein change

D36H

Other names

Canonical SPDI

NC_000014.9:80955785:G:C

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.

0.00140 (C)

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

1000 Genomes Project 0.00140

1000 Genomes Project 30x 0.00141

Trans-Omics for Precision Medicine (TOPMed) 0.00457

The Genome Aggregation Database (gnomAD) 0.00505

The Genome Aggregation Database (gnomAD), exomes 0.00517

Exome Aggregation Consortium (ExAC) 0.00602

Links

ClinGen: CA118191 OMIM: 603372.0001 dbSNP: rs61747482 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.
CEP128		-	-	GRCh38 GRCh37	86	145
TSHR		-	-	GRCh38 GRCh37	497	555

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.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Apr 25, 2017	RCV000122245.10
Familial hyperthyroidism due to mutations in TSH receptor	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000259846.6
THYROTROPIN RECEPTOR POLYMORPHISM	Benign (1)	no assertion criteria provided	Jan 1, 1999	RCV000006799.4
Hypothyroidism due to TSH receptor mutations	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000373195.6
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000870612.20

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303878.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Apr 25, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000708099.2 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSHR Number of individuals with the variant: 1 Sex: mixed
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005217812.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002822151.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: TSHR: BP4, BS2 Number of individuals with the variant: 7
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypothyroidism due to TSH receptor mutations Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000389121.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 17062880 Comment: 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, … (more) 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial hyperthyroidism due to mutations in TSH receptor Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000389122.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: 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, … (more) 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001012131.3 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Jan 01, 1999)	no assertion criteria provided Method: literature only	THYROTROPIN RECEPTOR POLYMORPHISM Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000026995.2 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015	Publications: PubMed (3) PubMed: 1955520‚ 9385128‚ 10037069 Comment on evidence: In a 29-year-old patient with Graves disease (GRD1; 275000), Heldin et al. (1991) identified a somatic substitution in the TSHR gene in thyroid tissue: a … (more) In a 29-year-old patient with Graves disease (GRD1; 275000), Heldin et al. (1991) identified a somatic substitution in the TSHR gene in thyroid tissue: a G-to-C transversion, resulting in an asp36-to-his (D36H) substitution. DNA in tissues originating from all 3 germ layers showed only the germline receptor sequence. Whether the mutation was directly implicated in the pathogenesis of the patient's autoimmune thyroid disorder or had functional significance in relation to the hyperthyroidism was unclear. In a review article, Paschke and Ludgate (1997) stated that the TSH receptor is a passive bystander in autoimmune hyperthyroidism, or Graves disease, and suggested that mutations in the TSHR gene are not involved in autoimmune disease pathogenesis. Simanainen et al. (1999) reported that the D36H substitution was not associated with Graves disease and is a polymorphic variant, with a frequency of approximately 5%. (less)
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086469.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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:

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases.	Peeters RP	European journal of endocrinology	2006	PMID: 17062880
Analysis of mutations in exon 1 of the human thyrotropin receptor gene: high frequency of the D36H and P52T polymorphic variants.	Simanainen J	Thyroid : official journal of the American Thyroid Association	1999	PMID: 10037069
The thyrotropin receptor in thyroid diseases.	Paschke R	The New England journal of medicine	1997	PMID: 9385128
A somatic point mutation in a putative ligand binding domain of the TSH receptor in a patient with autoimmune hyperthyroidism.	Heldin NE	The Journal of clinical endocrinology and metabolism	1991	PMID: 1955520
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSHR	-	-	-	-

Text-mined citations for rs61747482 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000369.5(TSHR):c.106G>C (p.Asp36His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61747482 ...