ClinVar Genomic variation as it relates to human health
NM_000549.5(TSHB):c.205C>T (p.Gln69Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000549.5(TSHB):c.205C>T (p.Gln69Ter)
Variation ID: 12687 Accession: VCV000012687.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.2 1: 115034015 (GRCh38) [ NCBI UCSC ] 1: 115576636 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 14, 2024 Dec 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000549.5:c.205C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000540.2:p.Gln69Ter nonsense NM_001277991.1:c.70C>T NP_001264920.1:p.Gln24Ter nonsense NC_000001.11:g.115034015C>T NC_000001.10:g.115576636C>T NG_015891.1:g.9222C>T - Protein change
- Q24*, Q69*
- Other names
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Q49*
- Canonical SPDI
- NC_000001.11:115034014:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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| TSHB | - | - |
GRCh38 GRCh37 |
63 | 75 | |
Conditions - Germline
| Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV000013524.30 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV003556008.2 | |
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TSHB-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2023 | RCV003415693.4 |
Submissions - Germline
| Classification
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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
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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
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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
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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. |
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Isolated thyroid-stimulating hormone deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002520987.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:11549695). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000012687 / PMID: 11297590). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Central hypothyroidism (present) , Decreased circulating cortisol level (present)
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Pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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TSHB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004107170.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TSHB c.205C>T variant is predicted to result in premature protein termination (p.Gln69*). This variant has been reported in the homozygous and compound heterozygous states … (more)
The TSHB c.205C>T variant is predicted to result in premature protein termination (p.Gln69*). This variant has been reported in the homozygous and compound heterozygous states in individuals with hypothyroidism (Bonomi et al. 2001. PubMed ID: 11297590; reported as Q49X in Karges et al. 2004. PubMed ID: 15297803). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115576636-C-T). Nonsense variants in TSHB are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12687/). Given the evidence, we interpret this variant as pathogenic. (less)
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Pathogenic
(Dec 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Isolated thyroid-stimulating hormone deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003823746.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004291975.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln69*) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gln69*) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the TSHB protein. This variant is present in population databases (rs121918670, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital hypothyroidism (PMID: 11297590, 11549695, 15297803). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Q49X. ClinVar contains an entry for this variant (Variation ID: 12687). This variant disrupts a region of the TSHB protein in which other variant(s) (p.Cys125Valfs*10) have been determined to be pathogenic (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Isolated thyroid-stimulating hormone deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914343.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The TSHB c.205C>T (p.Gln69Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln69Ter variant is described in two … (more)
The TSHB c.205C>T (p.Gln69Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln69Ter variant is described in two studies in which it is detected in a homozygous state in three individuals from two families with congenital hypothyroidism, two of whom are related (Bonomi et al. 2001; Vuissoz et al. 2001). The variant was also detected in a heterozygous state in both sets of parents and three unaffected siblings. Control data are unavailable for the p.Gln69Ter variant which is reported at a frequency of 0.000039 in the European (non-Finnish) population of the Genome Aggregation Database. Serum-TSH was extremely low in the affected homozygotes and stimulation with TRH failed to induce a TSH release. The p.Gln69Ter variant is predicted to result in a peptide lacking at least 50% of the C-terminal region of the protein. The truncated peptide does not contain the seat belt region of the protein, a region critical for the dimerization with the alpha-subunit and hence for the correct secretion of the mature TSH heterodimer. Based on the evidence, the p.Gln69Ter variant is classified as likely pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 01, 2001)
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no assertion criteria provided
Method: literature only
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HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033771.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 03, 2022 |
Comment on evidence:
Bonomi et al. (2001) reported an Egyptian girl with isolated central hypothyroidism (275100) due to homozygosity for a gln49-to-ter (Q49X) mutation in the TSHB gene. … (more)
Bonomi et al. (2001) reported an Egyptian girl with isolated central hypothyroidism (275100) due to homozygosity for a gln49-to-ter (Q49X) mutation in the TSHB gene. She was referred at 75 days of age for severe clinical signs of hypothyroidism, whose central origin was documented by normal serum TSH, low free T4 and free T3 levels, impaired TSH response to TRH, absence of 99Tc thyroidal uptake, and antithyroid autoantibodies. Ultrasound revealed a hypoplastic thyroid, whereas magnetic resonance imaging showed a hyperplastic pituitary. Interestingly, the sella computed tomography scan showed a completely normalized pituitary size at 21 months of age. At 8 years of age the patient was reinvestigated after 6-week L-T4 withdrawal. TSH values were highly variable depending on the measurement method used, whereas extremely high levels of circulating free glycoprotein alpha-subunit were recorded. Despite the fact that mutant Q49X TSHB lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity. The authors concluded that high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and possibly hyperplastic pituitary gland are hallmarks of isolated central hypothyroidism due to mutations of the TSHB gene. Vuissoz et al. (2001) reported severe isolated TSH deficiency in 2 children from the same consanguineous Turkish kindred. These affected children were homozygous for a C-to-T transition at nucleotide 654 of the TSHB subunit gene, leading to the conversion of a glutamine (CAG) to a premature stop codon (TAG) in codon 49 (Q49X). The resulting nascent peptide did not contain the seatbelt region (amino acid residues 88-105), a TSH-beta subunit region crucial for the dimerization with the alpha-subunit, and, hence, the correct secretion of the mature TSH heterodimer was hampered. Free T3, free T4, and basal TSH levels were extremely low in both affected individuals, and TRH stimulations failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency. (less)
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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. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
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| A RECURRENT MUTATION IN TSHB GENE UNDERLYING CENTRAL CONGENITAL HYPOTHYROIDISM UNDETECTABLE IN NEONATAL SCREENING. | Borges MF | Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo | 2019 | PMID: 31166470 |
| Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland. | Nicholas AK | Clinical endocrinology | 2017 | PMID: 27362444 |
| Congenital Central Hypothyroidism due to a Homozygous Mutation in the TSHβ Subunit Gene. | Grünert SC | Case reports in pediatrics | 2011 | PMID: 22606512 |
| Compound heterozygous and homozygous mutations of the TSHbeta gene as a cause of congenital central hypothyroidism in Europe. | Karges B | Hormone research | 2004 | PMID: 15297803 |
| New autosomal recessive mutation of the TSH-beta subunit gene causing central isolated hypothyroidism. | Vuissoz JM | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11549695 |
| Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. | Bonomi M | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11297590 |
| A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. | Medeiros-Neto G | The Journal of clinical investigation | 1996 | PMID: 8636437 |
Text-mined citations for rs121918670 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.