ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.152G>A (p.Cys51Tyr) (rs863223409)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200161 SCV000249627 pathogenic not provided 2015-04-14 criteria provided, single submitter clinical testing p.Cys51Tyr (C51Y) TGC>TAC: c.152 G>A in exon 3 of the ACVRL1 gene (NM_000020.2). The C51Y mutation in the ACVRL1 gene has been reported previously in several unrelated individuals with HHT (Klaus D et al., 1998; Olivieri C et al., 2002; Canzonieri C et al., 2014). C51Y results in a non-conservative amino acid substitution at a position that is conserved in mammalian species and participates in the formation of protein core interactions essential for protein stability (Scotti C et al., 2011). Moreover, functional studies show that the C51Y mutation results in failure to express at the cell surface and impaired signalling (Lux A et al., 1999; Ricard N et al., 2010). Mutations in nearby residues (G48R, G48E, W50G, W50C, T52A) have been reported in association with HHT, further supporting the functional importance of this region of the protein. Furthermore, the C51Y 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. In summary, C51Y in the ACVRL1 gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA panel(s).

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