12-51916107-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000020.3(ACVRL1):c.1120C>T(p.Arg374Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000020.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACVRL1 | NM_000020.3 | c.1120C>T | p.Arg374Trp | missense_variant | 8/10 | ENST00000388922.9 | NP_000011.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461192Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726758
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Telangiectasia, hereditary hemorrhagic, type 2 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 31, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2018 | PS3+PM2+PP4+PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 05, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 25, 2022 | PS4 PS3 PM2 PM1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 05, 2021 | PM1, PM2, PM5, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2024 | 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2021 | 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) - |
ACVRL1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 21, 2023 | 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. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 15, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at