ClinVar Miner

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

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Total submissions: 7
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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 Telangiectasia, hereditary hemorrhagic, type 2 2020-10-29 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000008737 SCV001156568 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-04-04 criteria provided, single submitter clinical testing The ACVRL1 c.1231C>T; p.Arg411Trp variant (rs121909287) is reported in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) and/or pulmonary arterial hypertension (PAH), and has been shown to co-segregate with disease (Abdalla 2003, Piao 2016, Trembath 2001, see link to ACVRL1 database and references therein). This variant is located in the catalytic domain of ACVRL1 and functional data indicate that it leads to impaired BMP9 signaling (Alaa El Din 2015, Piao 2016, Ricard 2010). The arginine at codon 411 has been described as a mutation hotspot (Lesca 2004), as both Arg411Pro and Arg411Gln are also frequently observed in HHT patients, both in our laboratory and as reported in the published literature (Lesca 2004, see ACVRL1 database and references therein). The p.Arg411Trp variant is also reported in ClinVar (Variation ID: 8251). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The ariginine at codon 411 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict this variant to be deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to ACVRL1 database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Abdalla SA et al. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J Med Genet. 2003 Jul;40(7):494-502. Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Hume AN et al. Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations. Mol Cell Biochem. 2013 Jan;373(1-2):247-57. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Piao C et al. Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. Clin Sci (Lond). 2016 Sep 1;130(17):1559-69. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12. Trembath RC et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001 Aug 2;345(5):325-34.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000008737 SCV001439398 likely pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-01-01 criteria provided, single submitter research PS3+PM2+PP4+PP5
Mayo Clinic Laboratories, Mayo Clinic RCV000199381 SCV001715008 pathogenic not provided 2020-06-04 criteria provided, single submitter clinical testing PS3, PS4_Moderate, PM1, PM2, PM5, PP1, PP3
OMIM RCV000008737 SCV000028946 pathogenic Telangiectasia, hereditary hemorrhagic, 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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