ClinVar Genomic variation as it relates to human health
NM_001059.3(TACR3):c.824G>A (p.Trp275Ter)
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_001059.3(TACR3):c.824G>A (p.Trp275Ter)
Variation ID: 66084 Accession: VCV000066084.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q24 4: 103656258 (GRCh38) [ NCBI UCSC ] 4: 104577415 (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 Dec 12, 2013 Feb 4, 2024 Jun 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001059.3:c.824G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001050.1:p.Trp275Ter nonsense NC_000004.12:g.103656258C>T NC_000004.11:g.104577415C>T NG_023344.1:g.68559G>A - Protein change
- W275*
- Other names
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- Canonical SPDI
- NC_000004.12:103656257: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00022
The Genome Aggregation Database (gnomAD), exomes 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00038
The Genome Aggregation Database (gnomAD) 0.00039
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
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 | ||
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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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TACR3 | - | - |
GRCh38 GRCh37 |
74 | 140 |
Conditions - Germline
Condition
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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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2021 | RCV000056319.35 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2022 | RCV000727615.13 |
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. |
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Pathogenic
(Jan 25, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000854875.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 11 with or without anosmia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000446801.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The TACR3 c.824G>A (p.Trp275Ter) variant is a stop-gained variant reported in four studies in which it is found in a total of 13 individuals with … (more)
The TACR3 c.824G>A (p.Trp275Ter) variant is a stop-gained variant reported in four studies in which it is found in a total of 13 individuals with isolated gonadotropin-releasing hormone (GnRH) deficiency, including in three homozygotes, in three compound heterozygotes, in five heterozygotes, and in two individuals showing digenic inheritance (Gianetti et al. 2010; Quaynor et al. 2011; Xu et al. 2011; Francou et al. 2011). The variant was absent from over 800 controls, but is reported at a frequency of 0.00093 in the European American population of the Exome Sequencing Project. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Trp275Ter variant is classified as pathogenic for isolated GnRH deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Mar 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067292.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the TACR3 gene demonstrated an apparently homozygous sequence change, c.824G>A, which results in the creation of a premature stop codon at … (more)
DNA sequence analysis of the TACR3 gene demonstrated an apparently homozygous sequence change, c.824G>A, which results in the creation of a premature stop codon at amino acid position 275, p.Trp275*. 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 TACR3 protein with potentially abnormal function. This sequence change has been previously described in male patients with normosmic idiopathic hypogonadotropic hypogonadism in both homozygous and compound heterozygous state (Francou et al., 2011 and Gianetti et al., 2010). This sequence change has been described in the gnomAD database with a population frequency of 0.032% (rs144292455). (less)
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Pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypogonadotropic hypogonadism 11 with or without anosmia
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018923.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 27, 2022)
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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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Invitae
Accession: SCV002153366.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp275*) in the TACR3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp275*) in the TACR3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TACR3 are known to be pathogenic (PMID: 20194706, 20332248, 22031817). This variant is present in population databases (rs144292455, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with idiopathic hypogonadotropic hypogonadism (PMID: 33363893). ClinVar contains an entry for this variant (Variation ID: 66084). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001872865.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29419413, 29886503, 31200363, 23643382, 21300340, 25525159, 26207952, 28436984, 30665703, 23329188, 30450471, 20332248, 26792935, 26239645, 22035731, 31980526, 34426522, 33363893, 31589614, 34055685, 22031817) (less)
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Pathogenic
(Jun 01, 2010)
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no assertion criteria provided
Method: literature only
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HYPOGONADOTROPIC HYPOGONADISM 11 WITHOUT ANOSMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000087488.3
First in ClinVar: Oct 19, 2013 Last updated: Dec 12, 2013 |
Comment on evidence:
In 3 male probands with normosmic hypogonadotropic hypogonadism (HH11; 614840) who were negative for mutation in at least 7 other HH-associated genes, Gianetti et al. … (more)
In 3 male probands with normosmic hypogonadotropic hypogonadism (HH11; 614840) who were negative for mutation in at least 7 other HH-associated genes, Gianetti et al. (2010) identified homozygosity for a c.824G-A transition in the TACR3 gene, resulting in a trp275-to-ter (W275X) substitution. In addition, W275X was found in heterozygosity in 4 more male probands with normosmic HH, who were also negative for mutation in 7 other HH-associated genes. One of the latter probands was also found to carry a synonymous variant (L58L) on the other allele of TACR3. There was evidence for neuroendocrine recovery in 3 of the 7 probands, with spontaneous fertility in 2 and increased LH pulses in 1 after discontinuation of sex steroid therapy. (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
HelpTitle | Author | Journal | Year | Link |
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Hypogonadotropic hypogonadism due to compound heterozygous mutations TACR3 in siblings. | Valsassina R | Clinical case reports | 2020 | PMID: 33363893 |
The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. | Quaynor SD | Fertility and sterility | 2011 | PMID: 22035731 |
Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations. | Francou B | PloS one | 2011 | PMID: 22031817 |
Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. | Xu N | Fertility and sterility | 2011 | PMID: 21300340 |
TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. | Gianetti E | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20332248 |
TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. | Young J | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20194706 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TACR3 | - | - | - | - |
Text-mined citations for rs144292455 ...
HelpRecord last updated Mar 17, 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.