ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.841G>T (p.Glu281Ter) (rs779485996)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465534 SCV000552407 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2016-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 281 (p.Glu281*) of the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This particular variant was reported in an individual with hereditary hemorrhagic telangiectasia who also had as second variant, c.1049-1G>A, in ACVRL1 (PMID: 20414677). It was unknown whether these two variants were on the same or different alleles. This variant has been reported in 2 independent individuals affected with hereditary hemorrhagic telangiectasia (PMID: 20414677, Invitae database). In both cases it co-occurred with a second variant in ACVRL1, c.1049-1G>A, that was proven to be in cis in one of the cases (Invitae database). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000578762 SCV000681034 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing The E281X variant in the ACVRL1 gene has been reported at least two patients with HHT, both of these patients also harbored ACVRL1 c.1049-1 G>A and these variants were on the same allele of the ACVRL1 gene (in cis) in one of these patients (Richards-Yutz et al., 2010; SCV000552407.1; Landrum et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the ACVRL1 gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014). Furthermore, the E281X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

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