ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1231C>T (p.Arg411Trp) (rs121909287)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199381 SCV000249635 pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing The R411W pathogenic variant in the ACVRL1 gene has been reported in association with HHT and PAH (Trembath et al., 2001; Abdalla et al., 2003; Lesca et al., 2004; Letteboer et al., 2005; Schulte et al., 2005). R411W is not observed in large population cohorts (Lek et al., 2016). The R411W 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies show that R411W results in defective BMP9 response and impaired ALK1 activity due to abnormal ALK1 trafficking (Ricard et al., 2010; Hume et al., 2013). Lastly, missense variants at the same and nearby residues (R411Q, E407G) have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV000008737 SCV000552419 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 411 of the ACVRL1 protein (p.Arg411Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs121909287, ExAC no frequency). This variant has been reported in several individuals and families affected with hemorrhagic telangiectasia (PMID: 11484689, 15024723, 15880681). ClinVar contains an entry for this variant (Variation ID: 8251). Experimental studies have shown that this missense change causes lack of response to BMP9 stimulation and protein mislocalization disrupting ACVRL1 protein function (PMID: 20501893, 23124896, 26176610). Two other different missense substitution at this codon (p.Arg411Pro, p.Arg411Gln) have been determined to be pathogenic (PMID: 8640225, 14684682, 15024723, 20501893). This suggests that the arginine residue is critical for ACVRL1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008737 SCV000028946 pathogenic Hereditary hemorrhagic telangiectasia type 2 2008-06-01 no assertion criteria provided literature only
OMIM RCV000008738 SCV000028947 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia 2008-06-01 no assertion criteria provided literature only

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