ClinVar Miner

Submissions for variant NM_001059.3(TACR3):c.824G>A (p.Trp275Ter)

gnomAD frequency: 0.00039  dbSNP: rs144292455
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000056319 SCV000446801 pathogenic Hypogonadotropic hypogonadism 11 with or without anosmia 2017-04-27 criteria provided, single submitter clinical testing 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.
Eurofins Ntd Llc (ga) RCV000727615 SCV000854875 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000727615 SCV001872865 pathogenic not provided 2022-06-06 criteria provided, single submitter clinical testing 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)
Revvity Omics, Revvity RCV000056319 SCV002018923 pathogenic Hypogonadotropic hypogonadism 11 with or without anosmia 2021-10-04 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000727615 SCV002067292 pathogenic not provided 2019-03-29 criteria provided, single submitter clinical testing 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).
Invitae RCV000727615 SCV002153366 pathogenic not provided 2022-05-27 criteria provided, single submitter clinical testing 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.
OMIM RCV000056319 SCV000087488 pathogenic Hypogonadotropic hypogonadism 11 with or without anosmia 2010-06-01 no assertion criteria provided literature only

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