PS3, PM3_Strong
ClinVar Genomic variation as it relates to human health
NM_000549.5(TSHB):c.373del (p.Cys125fs)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000549.5(TSHB):c.373del (p.Cys125fs)
Variation ID: 437070 Accession: VCV000437070.22
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 1p13.2 1: 115034183 (GRCh38) [ NCBI UCSC ] 1: 115576804 (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 Aug 28, 2017 Oct 8, 2024 Sep 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000549.5:c.373del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000540.2:p.Cys125fs frameshift NM_000549.4:c.373delT NM_001277991.1:c.238del NP_001264920.1:p.Cys80fs frameshift NC_000001.11:g.115034183del NC_000001.10:g.115576804del NG_015891.1:g.9390del - Protein change
- C125fs, C80fs
- Other names
- -
- Canonical SPDI
- NC_000001.11:115034182:T:
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00016
The Genome Aggregation Database (gnomAD) 0.00017
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TSHB | - | - |
GRCh38 GRCh37 |
63 | 75 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 15, 2022 | RCV000503516.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 28, 2021 | RCV002463363.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 26, 2024 | RCV000598622.11 |
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
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Isolated thyroid-stimulating hormone deficiency
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799170.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS3, PM3_Strong
|
|
|
Pathogenic
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Isolated thyroid-stimulating hormone deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003823735.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000709855.5
First in ClinVar: Apr 02, 2018 Last updated: Oct 08, 2024 |
Comment:
Published functional studies demonstrate a damaging effect as c.373delT is shown to be biologically inactive (PMID: 8636437); Frameshift variant predicted to result in abnormal protein … (more)
Published functional studies demonstrate a damaging effect as c.373delT is shown to be biologically inactive (PMID: 8636437); Frameshift variant predicted to result in abnormal protein length as the last 14 amino acids are replaced with 9 different amino acids; This variant is associated with the following publications: (PMID: 8636437, 22606512, 27362444, 31166470, 31703413, 31980526, 31384098, 15297803, 31589614, 36001021, 34780050) (less)
|
|
|
Pathogenic
(May 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Isolated thyroid-stimulating hormone deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002782397.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003302470.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys125Valfs*10) 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.Cys125Valfs*10) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the TSHB protein. This variant is present in population databases (rs755485552, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of congenital hypothyroidism (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). It has also been observed to segregate with disease in related individuals. This variant is also known as C105V or 313delT. ClinVar contains an entry for this variant (Variation ID: 437070). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHB function (PMID: 8636437). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 01, 2002)
|
no assertion criteria provided
Method: literature only
|
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033770.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Medeiros-Neto et al. (1996) described 2 related Brazilian sibships with congenital nongoitrous hypothyroidism (275100) due to a circulating form of biologically inactive TSH containing a … (more)
Medeiros-Neto et al. (1996) described 2 related Brazilian sibships with congenital nongoitrous hypothyroidism (275100) due to a circulating form of biologically inactive TSH containing a mutation in the TSH-beta subunit. The parents in each case were consanguineous. The affected children had low thyroid hormone levels and radioactive iodine uptake in the thyroid gland associated with measurable serum TSH. TSH secretion stimulated by thyrotropin-releasing hormone (613879) did not increase thyroid hormone production in these patients as compared to their unaffected sibs, suggesting to the authors that the mutant TSH was biologically inactive in vivo. Recombinant TSH harboring the mutation was shown to be biologically inactive in an in vitro bioassay. The mutation was found to be a homozygous 1-bp deletion (T) from codon 105 (TGT) of the TSHB gene, converting a cysteine to a valine residue (C105V) and yielding an additional 8-amino acid nonhomologous peptide extension on the mutant protein. Doeker et al. (1998) reported a homozygous 1-bp (T) deletion at nucleotide 410 in codon 105 of the TSHB gene in a 5-month-old infant of nonconsanguineous parents. The child had severe central hypothyroidism with undetectable serum levels of T3 and T4 in combination with an undetectable baseline TSH level. The mutation caused a frameshift with a premature stop at codon 114. The truncated TSHB peptide lacked the terminal 5 amino acids. The nucleotide number in this mutation has variously been described as 313 or 410. Brumm et al. (2002) stated that this mutation, which they referred to as 313delT (C105V), is the most frequent TSHB mutation and had been described in 6 apparently unrelated families. They investigated the frequency and possible monophyletic origin of the different 313delT alleles of 3 affected German families. Haplotype analysis of 5 polymorphic SNP loci in the TSHB region revealed the presence of 7 different haplotypes in the general population. In all 6 parental lines, the mutation occurred on the same haplotype. Extending the haplotype by 2 flanking microsatellite markers led to a mutation age estimate of approximately 150 generations. In 500 unrelated individuals from the general population, the authors did not detect any 313delT alleles, suggesting a population heterozygote carrier frequency of less than 1 in 170 with more than 95% probability. The data suggested a monophyletic origin of the TSHB 313delT mutation from a common ancestor and no significant population prevalence. (less)
|
|
|
Pathogenic
(Dec 28, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Secondary hypothyroidism
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064500.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
DNA sequence analysis of the TSHB gene demonstrated a single base pair deletion in exon 3, c.373del. This pathogenic sequence change results in an amino … (more)
DNA sequence analysis of the TSHB gene demonstrated a single base pair deletion in exon 3, c.373del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the change, p.Cys125Valfs*10. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHB protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of o.031% in the non-Finnish European subpopulation (dbSNP rs755485552). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple individuals with TSHB-related hypothyroidism (PMID: 31166470, 22606512, 31703413, 15297803, 27362444). (less)
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect as c.373delT is shown to be biologically inactive (PMID: 8636437); Frameshift variant predicted to result in abnormal protein length as the last 14 amino acids are replaced with 9 different amino acids; This variant is associated with the following publications: (PMID: 8636437, 22606512, 27362444, 31166470, 31703413, 31980526, 31384098, 15297803, 31589614, 36001021, 34780050)
Comment:
This sequence change creates a premature translational stop signal (p.Cys125Valfs*10) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the TSHB protein. This variant is present in population databases (rs755485552, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of congenital hypothyroidism (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). It has also been observed to segregate with disease in related individuals. This variant is also known as C105V or 313delT. ClinVar contains an entry for this variant (Variation ID: 437070). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHB function (PMID: 8636437). For these reasons, this variant has been classified as Pathogenic.
Comment:
DNA sequence analysis of the TSHB gene demonstrated a single base pair deletion in exon 3, c.373del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the change, p.Cys125Valfs*10. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHB protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of o.031% in the non-Finnish European subpopulation (dbSNP rs755485552). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple individuals with TSHB-related hypothyroidism (PMID: 31166470, 22606512, 31703413, 15297803, 27362444).
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:
PS3, PM3_Strong
Comment:
Published functional studies demonstrate a damaging effect as c.373delT is shown to be biologically inactive (PMID: 8636437); Frameshift variant predicted to result in abnormal protein length as the last 14 amino acids are replaced with 9 different amino acids; This variant is associated with the following publications: (PMID: 8636437, 22606512, 27362444, 31166470, 31703413, 31980526, 31384098, 15297803, 31589614, 36001021, 34780050)
Comment:
This sequence change creates a premature translational stop signal (p.Cys125Valfs*10) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the TSHB protein. This variant is present in population databases (rs755485552, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of congenital hypothyroidism (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). It has also been observed to segregate with disease in related individuals. This variant is also known as C105V or 313delT. ClinVar contains an entry for this variant (Variation ID: 437070). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHB function (PMID: 8636437). For these reasons, this variant has been classified as Pathogenic.
Comment:
DNA sequence analysis of the TSHB gene demonstrated a single base pair deletion in exon 3, c.373del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the change, p.Cys125Valfs*10. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHB protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of o.031% in the non-Finnish European subpopulation (dbSNP rs755485552). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple individuals with TSHB-related hypothyroidism (PMID: 31166470, 22606512, 31703413, 15297803, 27362444).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Congenital central hypothyroidism due to homozygous thyrotropin beta 313 Delta T mutation is caused by a Founder effect. | Brumm H | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12364478 |
| Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance. | Doeker BM | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9589689 |
| 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 rs755485552 ...
HelpThese 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 08, 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.