ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1336C>T (p.Gln446Ter) (rs1064794217)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479233 SCV000568238 likely pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing The Q446X variant in the ACVRL1 gene has been reported in one individual with HHT (McDonald et al., 2011). The Q446X variant is predicted to cause loss of normal protein function by protein truncation, as the last 58 amino acid residues of the protein are lost. Other nonsense variants in the ACVRL1 gene, including several downstream, have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014). Furthermore, the Q446X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, this variant lacks a sufficient number of probands, segregation data, and functional studies to be able to definitively determine is pathogenicity.
Invitae RCV000531463 SCV000639392 pathogenic Hereditary hemorrhagic telangiectasia type 2 2017-07-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ACVRL1 gene (p.Gln446*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 58 amino acids of the ACVRL1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hemorrhagic telangiectasia (PMID: 21158752). ClinVar contains an entry for this variant (Variation ID: 419979). A different truncation downstream of this variant (p.Arg479*) has been determined to be pathogenic (PMID: 15024723, 15065824, 15517393, 15712271, 16429404, 16540754, 18673552, 21158752, 23722869). This suggests that deletion of this region of the ACVRL1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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