ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.360+5G>A (rs1060501417)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000405 SCV001157199 likely pathogenic Hereditary hemorrhagic telangiectasia type 1 2019-02-06 criteria provided, single submitter clinical testing The ENG c.360+5G>A variant is reported in the literature in an individual with a clinical diagnosis of HHT (Letteboer 2005). In addition, other changes affecting this +5 position (c.360+4_7delAGTG, c.360+5G>C, c.360+5G>T), are also reported in individuals suspected to have HHT (Gedge 2007, Lux 2013). The c.360+5G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a well conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by abolishing the nearby canonical donor splice site. Based on available information, the c.360+5G>A variant is considered to be likely pathogenic. REFERENCES Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Lux A et al. HHT diagnosis by Mid-infrared spectroscopy and artificial neural network analysis. Orphanet J Rare Dis. 2013 Jun 27;8:94.
Invitae RCV001217648 SCV001389497 uncertain significance Hereditary hemorrhagic telangiectasia 2020-03-04 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15517393, Invitae). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001000405 SCV001441151 likely pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-01-01 criteria provided, single submitter research PM2+PP3+PP4

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