ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.998G>T (p.Ser333Ile) (rs863223413)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198205 SCV000249632 pathogenic not provided 2014-06-11 criteria provided, single submitter clinical testing The S333I mutation in the ACVRL1 gene has been reported previously in several unrelated patients with HHT (Berg J et al., 1997; Lux A et al., 2013). Functional studies of the S333I mutation showed a dominant-negative effect and suppressed normal ACVRL1 protein activity (Abdalla S et al., 2000; Gu Y et al 2006). The S333I 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. The S333I mutation is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a mutation in this residue (S333G) and mutations in nearby residues (D330N, D330Y, F331S, N335H) have been reported in association with HHT, further supporting the functional importance of this residue and region of the protein. This variant was found in ACVRL1,HHT-ARRHYTHMIA panel(s).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000198205 SCV000602408 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762899 SCV000893306 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-10-31 criteria provided, single submitter clinical testing

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