ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1435C>T (p.Arg479Ter) (rs1057517944)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414291 SCV000491144 pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing The R479X variant in the ACVRL1 gene has been reported previously in several unrelated individuals with HHT, both with and without an additional diagnosis of pulmonary hypertension (Lesca et al., 2004; Abdalla et al., 2004; Letteboer et al., 2005; Olivieri et al., 2006; Lenato et al., 2006; Gedge et al., 2007; Fontalba et al., 2008; Chen et al., 2013; Canzonieri et al., 2014; Komiyama et al., 2014). Moreover, Chen et al. (2013) reported that the R479X variant segregated with HHT in a large Chinese family. Furthermore, the R479X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R479X is predicted to cause loss of normal protein function by protein truncation and loss of the last 25 amino acids of the protein. In addition, other nonsense variants in the ACVRL1 gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000533545 SCV000602411 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2019-10-09 criteria provided, single submitter clinical testing The ACVRL1 c.1435C>T; p.Arg479Ter variant (rs1057517944) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT; Abdalla 2004 and 2005, Canzonieri 2014, Chen 2013, Fontalba 2008, Gedge 2007, Komiyama 2014, Lenato 2006, Lesca 2004, Letterboer 2005, Olivieri 2006, Yan 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 372722), and is only observed on one allele in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the ACVRL1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein, and functional analyses of the variant protein demonstrate a loss of ligand-induced receptor signaling and down-regulation of the protein (Garamszeg 2001). Additionally, another downstream truncating variant, c.1468C>T; p.Gln490Ter, has been reported in multiple patients with HHT (Girerd 2010, Machado 2015, Trembath 2001) and is considered pathogenic in ClinVar (Variation ID:426040). Based on available information, the c.1435C>T; p.Arg479Ter variant is considered to be pathogenic. References: Abdalla SA et al. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J. 2004 Mar;23(3):373-7. Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005 Mar;25(3):320-1. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014 Jan;16(1):3-10. Chen YJ et al. Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. Eur J Clin Invest. 2013 Oct;43(10):1016-24. Fontalba A et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2008 Aug 1;9:75. Garamszegi N et al. Transforming growth factor beta receptor signaling and endocytosis are linked through a COOH terminal activation motif in the type I receptor. Mol Biol Cell. 2001 Sep;12(9):2881-93. 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. Girerd B et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010 Apr 15;181(8):851-61. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014 Jan;59(1):37-41. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Letterboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. Olivieri C et al. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genet Med. 2006 Mar;8(3):183-90. Trembath RC et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001 Aug 2;345(5):325-34. Yan ZM et al. A novel mutation in ALK-1 causes hereditary hemorrhagic telangiectasia type 2. J Dent Res. 2006 Aug;85(8):705-10.
Invitae RCV000533545 SCV000639395 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-10-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the ACVRL1 mRNA at codon 479 (p.Arg479*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 25 amino acids of the ACVRL1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15024723, 15065824, 15517393, 15712271, 16429404, 16540754, 18673552, 21158752, 23722869). ClinVar contains an entry for this variant (Variation ID: 372722). A different missense substitution at this codon (p.Arg479Gln) has been determined to be pathogenic (PMID: 16470787, 16705692, 20501893, 21158752). This suggests that the arginine residue is critical for ACVRL1 protein function that the loss of this residue and the remaining downstream residues may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000533545 SCV001439404 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4
Mayo Clinic Laboratories, Mayo Clinic RCV000414291 SCV001715009 pathogenic not provided 2019-12-17 criteria provided, single submitter clinical testing PVS1_moderate, PS4, PM2, PP1_Strong
Genetics,Medical University of Vienna RCV000513497 SCV000346044 likely pathogenic Hereditary hemorrhagic telangiectasia type 1 no assertion criteria provided clinical testing
Medical & Molecular Genetics Group,University of Lincoln RCV000488776 SCV000576343 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia no assertion criteria provided literature only

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