ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1120C>T (p.Arg374Trp) (rs28936401)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000330901 SCV000329736 pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing The R374W pathogenic variant in the ACVRL1 gene has been previously reported in several unrelated individuals with clinical diagnoses of HHT (Berg et al., 1997; Kjeldsen et al., 2001; Abdalla et al., 2004; Sanz-Rodriguez et al., 2004; Letteboer et al., 2005; Olivieri et al., 2007; Gedge et al., 2007; Nishida et al., 2012; Canzonieri et al., 2014), including at least one individual who also had pulmonary hypertension (Abdalla et al., 2004). Furthermore, R374W was found to segregate with disease in 15 additional relatives from two families with HHT (Kjeldsen et al., 2001; Sanz-Rodriguez et al., 2004). This variant is also not observed in large population cohorts (Lek et al., 2016). Additionally, R374W results in a non-conservative amino acid, and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies have demonstrated that the ALK1 protein harboring R374W is unresponsive to BMP9 and TGF-beta signaling and does not induce SMAD1/5 phosphorylation (Gu et al., 2006; Ricard et al., 2010). In addition, a variant in the same residue (R374Q) has been reported in several other individuals with HHT (Abdalla et al., 2003; Letteboer et al., 2005; Gedge et al., 2007; Olivieri et al., 2007; Fontalba et al., 2008; Chen et al., 2013; Heimdal et al., 2016), and functional studies of R374Q suggest that this variant also impairs the BMP9 signaling response (Ricard et al., 2010), further supporting the functional importance of this residue of the protein.In summary, R374W in the ACVRL1 gene is interpreted as a pathogenic variant.
Invitae RCV000008733 SCV000552398 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 374 of the ACVRL1 protein (p.Arg374Trp). 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 (ExAC no frequency). This variant has been reported in numerous individuals and families affected with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9245985, 23722869,15375013, 22991266, 15065824, 23805858). ClinVar contains an entry for this variant (Variation ID: 8249). A different missense substitution at this codon (p.Arg374Gln) has been determined to be pathogenic (PMID: 12700602, 18285823, 21158752, 25970827). This suggests that the arginine residue is critical for ACVRL1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this variant affects several aspects of protein function (PMID: 20501893, 16282348, 15375013). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000330901 SCV000602415 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing The ACVRL1 c.1120C>T; p.Arg374Trp variant (rs28936401) has been shown to segregate in multiple families affected with symptoms of hereditary hemorrhagic telangiectasia (Berg 1997, Canzonieri 2014, Harrison 2003, Lesca 2008, Nishida 2012, Ricard 2010, see HHT database link), as well as identified in a number of affected patients in our laboratory. This variant is reported in ClinVar as pathogenic (Variation ID: 8249), and observed in general population databases at a very low frequency (1/30960 alleles, Genome Aggregation Database). Arginine 374 is located in exon 8 of ACVRL1, which has been described as a hotspot for pathogenic variants (Olivieri 2002). Taken together, this variant is considered pathogenic. REFERENCES Link to ACVRL1 HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php Link to ClinVar database for p.Arg374Trp: https://www.ncbi.nlm.nih.gov/clinvar/variation/8249/ Berg et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997; 61(1): 60-67. Canzonieri et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014; 16(1): 3-10. Harrison et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003; 40(12): 865-871. Lesca et al. Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. Eur J Hum Genet. 2008; 16(6): 742-749. Nishida et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012; 158A(11): 2829-2834. Olivieri et al. Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. J Med Genet. 2002; 39(7): E39. Ricard et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010; 116(9): 1604-1612.
Fulgent Genetics,Fulgent Genetics RCV000008733 SCV000893307 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000008733 SCV000028942 pathogenic Hereditary hemorrhagic telangiectasia type 2 2008-06-01 no assertion criteria provided literature only
OMIM RCV000008734 SCV000028943 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia 2008-06-01 no assertion criteria provided literature only
Medical & Molecular Genetics Group,University of Lincoln RCV000008734 SCV000576330 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia no assertion criteria provided literature only

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