ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.269G>A (p.Cys90Tyr) (rs863223410)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196221 SCV000249628 pathogenic not provided 2015-03-11 criteria provided, single submitter clinical testing p.Cys90Tyr (C90Y) TGC>TAC: c.269 G>A in exon 3 of the ACVRL1 gene (NM_000020.2). The C90Y mutation in the ACVRL1 gene has been reported previously in association with HHT and was absent from at least 144 control individuals (Lesca et al., 2006; Gedge et al., 2007). Similarly, the C90Y mutation was not observed in approximately 6,400 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 C90Y variant 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 conserved across species. Furthermore, the C90 residue participates in disulfide bonding and is thought to be important to the protein structure/function (Scotti et al., 2011). Another mutation in the same residue (C90W), as well as mutations in nearby residues (C89Y, C95R, N96D) have been reported in association with HHT, further supporting the functional importance of this residue and of thisregion of the protein. In summary, C90Y in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA panel(s).
NIHR Bioresource Rare Diseases, University of Cambridge RCV001262078 SCV001439463 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-01-01 criteria provided, single submitter research PM2+PP2+PP4

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