ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507091 SCV000602411 pathogenic not specified 2016-12-19 criteria provided, single submitter clinical testing
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).
Genetics,Medical University of Vienna RCV000513497 SCV000346044 likely pathogenic Osler hemorrhagic telangiectasia syndrome no assertion criteria provided clinical testing
Invitae RCV000533545 SCV000639395 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-08-14 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.
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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