ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1345C>T (p.Pro449Ser)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001062489 SCV001227292 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 449 of the ACVRL1 protein (p.Pro449Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hereditary hemorrhagic telangiectasia in a family (Invitae) and has been reported in an unrelated individual with clinical features of this disease (PMID: 20414677). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Pro449 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 18673552, 16542389), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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