Submissions for variant NM_000020.3(ACVRL1):c.1120C>T (p.Arg374Trp)

dbSNP: rs28936401

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000330901	SCV000329736	pathogenic	not provided	2021-10-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); 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 silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 8249; ClinVar); This variant is associated with the following publications: (PMID: 22991266, 14684682, 17786384, 17384219, 16542389, 15517393, 9245985, 11170071, 18285823, 25892364, 26387786, 15065824, 23722869, 15375013, 23805858, 29631995, 31400083, 30578383, 31727138, 32503579, 32573726, 20501893, 16282348)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000008733	SCV000552398	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 374 of the ACVRL1 protein (p.Arg374Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 9245985, 15065824, 15375013, 22991266, 23722869, 23805858). ClinVar contains an entry for this variant (Variation ID: 8249). 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: 15375013, 16282348, 20501893). This variant disrupts the p.Arg374 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12700602, 18285823, 21158752, 25970827). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000008733	SCV000602415	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2022-05-05	criteria provided, single submitter	clinical testing	The ACVRL1 c.1120C>T; p.Arg374Trp variant (rs28936401) has been shown to co-segregate with disease in multiple families affected with symptoms of HHT (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 by our laboratory. This variant is reported in ClinVar as pathogenic (Variation ID: 8249). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 374 is located in exon 8 of ACVRL1, which has been described as a hotspot for pathogenic variants (Olivieri 2002). Based on available information, this variant is considered to be pathogenic. References: Link to ACVRL1 HHT database: http://arup.utah.edu/database/ACVRL1/ACVRL1_display.php 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	Telangiectasia, hereditary hemorrhagic, type 2	2021-08-31	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000008733	SCV001439395	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2018-01-01	criteria provided, single submitter	research	PS3+PM2+PP4+PP5
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000008733	SCV001976833	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2021-10-05	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000008733	SCV002583654	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2022-08-25	criteria provided, single submitter	clinical testing	PS4 PS3 PM2 PM1
Ambry Genetics	RCV002433448	SCV002748397	pathogenic	Cardiovascular phenotype	2022-01-15	criteria provided, single submitter	clinical testing	The p.R374W pathogenic mutation (also known as c.1120C>T), located in coding exon 7 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 1120. The arginine at codon 374 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and families with hereditary hemorrhagic telangiectasia (Berg JN et al. Am. J. Hum. Genet., 1997 Jul;61:60-7; Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87; Zhao Y et al. Mol Genet Genomic Med. 2019 09;7(9):e893; Shovlin CL et al. Blood. 2020 10;136(17):1907-1918). In addition, this mutation, located in the kinase domain of ACVRL1, showed decreased enzyme activity in in vitro functional studies (Fernandez-L A et al. Hum. Mutat., 2006 Mar;27:295; Gu Y et al. Blood, 2006 Mar;107:1951-4; Ricard N et al. Blood, 2010 Sep;116:1604-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV004547469	SCV004120576	pathogenic	ACVRL1-related disorder	2023-09-21	criteria provided, single submitter	clinical testing	The ACVRL1 c.1120C>T variant is predicted to result in the amino acid substitution p.Arg374Trp. This variant has been documented numerous times in individuals with hereditary hemorrhagic telangiectasia (HHT) (Kitayama et al. 2021. PubMed ID: 34872578; Table S1 in McDonald et al. 2020. PubMed ID: 32300199; Supplementary Table in Nishida et al. 2012. PubMed ID: 22991266). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/8249/). This variant is interpreted as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000330901	SCV005199484	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000008733	SCV000028942	pathogenic	Telangiectasia, hereditary hemorrhagic, 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
Rare Disease Genomics Group, St George's University of London	RCV000008734	SCV000576330	pathogenic	Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia		no assertion criteria provided	literature only