ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1270C>A (p.Pro424Thr) (rs1085307419)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000810385 SCV000950581 likely pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 424 of the ACVRL1 protein (p.Pro424Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 9245985) and pulmonary arterial hypertension (PMID: 18159113, Invitae). ClinVar contains an entry for this variant (Variation ID: 426028). 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. Variants that disrupt the p.Pro424 amino acid residue in ACVRL1 have been observed in affected individuals (PMID: 9245985, 18159113, 15712271, 22781769). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Medical & Molecular Genetics Group,University of Lincoln RCV000488652 SCV000576336 pathogenic Primary pulmonary hypertension no assertion criteria provided literature only

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