ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.986G>A (p.Arg329His) (rs863223412)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197384 SCV000249631 pathogenic not provided 2015-05-07 criteria provided, single submitter clinical testing p.Arg329His (R329H) CGC>CAC: c.986 G>A in exon 7 of the ACVRL1 gene (NM_000020.2). The R329H mutation in the ACVRL1 gene has been reported in at least two unrelated individuals with HHT (Abdalla S et al., 2003; Argyriou L et al., 2005). Furthermore, the R329H 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. R329H results in a conservative amino acid substitution at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, mutations in nearby residues (H328Y, H328P, H328Q, D330Y, D330N, D330H) have been reported in association with HHT, further supporting the functional importance of this region of the protein. In summary, R329H in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-PANCARD
Invitae RCV000531199 SCV000639412 likely pathogenic Hereditary hemorrhagic telangiectasia type 2 2017-07-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 329 of the ACVRL1 protein (p.Arg329His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several unrelated individuals affected with hemorrhagic telangiectasia (PMID: 12700602, 16123970, Invitae). ClinVar contains an entry for this variant (Variation ID: 212801). 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. In summary, this variant is a rare missense change that is predicted to be deleterious and has been observed in multiple affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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