ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1377+1G>A (rs863223406)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197808 SCV000249623 pathogenic not provided 2015-04-22 criteria provided, single submitter clinical testing IVS9+1 G>A : c.1377+1 G>A in intron 9 of the ACVRL1 gene (NM_000020.2). The c.1377+1 G>A mutation has been reported previously in association with HHT, and was absent from 100 control alleles (Kuehl H et al., 2005). Furthermore, the c.1377+1 G>A mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice donor site in intron 9 and is predicted to cause abnormal gene splicing. Other splice site mutations in the ACVRL1 gene have been reported in association with HHT. In summary, c.1377+1 G>A in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA panel(s).
Invitae RCV000689218 SCV000816858 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-06-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 9) of the ACVRL1 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15712270, 19508727, 21158752, Invitae). ClinVar contains an entry for this variant (Variation ID: 212794). 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. For these reasons, this variant has been classified as Pathogenic.

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