ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1359_1360delinsT (p.Arg454fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV003994639 SCV004812384 likely pathogenic Hereditary hemorrhagic telangiectasia 2023-03-30 criteria provided, single submitter clinical testing This sequence change in ACVRL1 is a frameshift variant that may cause a premature stop codon, p.(Arg454Glyfs*11) that is predicted to escape nonsense-mediated decay and remove <10% of the protein, however it is a truncation of a functionally important region (protein kinase domain) in a gene where loss-of-function is an established disease mechanism (PMID: 16282348). This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this multi-nucleotide variant has not been reported in the literature in any individuals with ACVRL1-related disease. It has been identified in at least one proband with a clinical diagnosis of hereditary haemorrhagic telangiectasia (Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PS4_Supporting, PM2_Supporting.

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