ClinVar Genomic variation as it relates to human health

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.

Identified in individuals from various ethnic backgrounds with HHT and/or PAH (Trembath et al., 2001; Abdalla et al., 2003; Lesca et al., 2004; Kuehl et al., 2005; Letteboer et al., 2005; Schulte et al., 2005; Piao et al., 2016; Han et al., 2020; Shovlin et al., 2020; Kitayama et al., 2021; Zhang et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in defective BMP9 response and impaired ALK1 activity due to abnormal ALK1 trafficking (Ricard et al., 2010; Hume et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15879500, 16542389, 25312062, 15024723, 26176610, 27316748, 15517393, 15880681, 15712270, 12114496, 12700602, 23124896, 28823282, 30578397, 32573726, 20501893, 29631995, 32300199, 32954380, 34966542, 32503579, 34872578, 11484689)

PS3+PM2+PP4+PP5

PP1, PP3, PM1, PM2, PS3, PS4_moderate

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 411 of the ACVRL1 protein (p.Arg411Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemorrhagic telangiectasia (PMID: 11484689, 15024723, 15880681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 20501893, 23124896, 26176610). This variant disrupts the p.Arg411 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8640225, 14684682, 15024723, 20501893). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This sequence change in ACVRL1 is predicted to replace arginine with tryptophan at codon 411 (p.(Arg411Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the protein kinase domain. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT) and pulmonary hypertension, and segregates with HHT in multiple families (PMID: 11484689, 15024723). BMP9 ligand binding assays in cell lines showed defective signalling indicating that this variant impacts protein function (PMID: 20501893). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Another missense variant c.1232G>A, p.Arg411Gln in the same codon has been classified as pathogenic for HHT (ClinVar ID: 8243). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM5, PS3_Supporting, PM2_Supporting, PP1, PP3.

The p.R411W pathogenic mutation (also known as c.1231C>T), located in coding exon 7 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1231. The arginine at codon 411 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) with segregation with disease in a few families. In addition, this mutation has also been reported in association with pulmonary arterial hypertension with or without HHT (Trembath RC et al. N. Engl. J. Med., 2001 Aug;345:325-34; Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87; Zhang GS et al. Chin. Med. J., 2004 Jun;117:808-12; Song J et al. Clin Sci (Lond). 2016 11;130(22):2043-2052; Zhu N et al. Circ Genom Precis Med. 2018 04;11(4):e001887). In vitro functional studies indicate that mutations at this codon 411 impair ALK1 activity (Ricard N et al. Blood, 2010 Sep;116:1604-12; Alaa El Din F et al. PLoS ONE, 2015 Jul;10:e0132111). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Variant interpreted as not provided and reported on 04-27-2017 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.