ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1378-69C>A

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV004766195 SCV005378401 uncertain significance not provided 2024-04-19 criteria provided, single submitter clinical testing RNA studies show a damaging effect through partial retention of intervening sequence 9 (IVS9) (PMID: 30244195); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 30244195)
Labcorp Genetics (formerly Invitae), Labcorp RCV005104950 SCV005824218 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2025-01-27 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the ACVRL1 gene. It does not directly change the encoded amino acid sequence of the ACVRL1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 30244195; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 3364590). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV005104950 SCV005875537 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2023-12-18 criteria provided, single submitter clinical testing The ACVRL1 c.1378-69C>A variant is reported in the literature in individuals affected with hereditary haemorrhagic telangiectasia (Wooderchak-Donahue 2018). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is an intronic variant, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Functional analyses of patient RNA demonstrate partial retention of intron 9 leading to a frameshift, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay (Wooderchak-Donahue 2018). Based on available information, this variant is considered to be pathogenic. References: Wooderchak-Donahue WL et al. Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. J Med Genet. 2018 Dec;55(12):824-830. PMID: 30244195.

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