Submissions for variant NM_000020.3(ACVRL1):c.430C>T (p.Arg144Ter)

dbSNP: rs758683062

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472148	SCV000552408	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg144*) in the ACVRL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACVRL1 are known to be pathogenic (PMID: 15879500). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension (PMID: 12700602, 15024723, 15879500, 15880681, 16429404, 16540754, 19555857, 23722869). ClinVar contains an entry for this variant (Variation ID: 212804). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000472148	SCV000883352	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2021-09-15	criteria provided, single submitter	clinical testing	The ACVRL1 c.430C>T; p.Arg144Ter variant (rs758683062) is reported in the literature in multiple individuals diagnosed with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension (Abdalla 2003, Abdalla 2005, Brusgaard 2004, Canzonieri 2014, Giordano 2006, Kjeldsen 2005, Komiyama 2014, Lesca 2004, Machado 2009, Olivieri 2007, Schulte 2005). This variant is reported in ClinVar as pathogenic by multiple laboratories (Variation ID: 212804), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Abdalla SA et al. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003; 11(4):279-87. PMID: 12700602. Abdalla SA et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005; 25(3):320-1. PMID: 15712271. Brusgaard K et al. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2004; 66(6):556-61. PMID: 15521985. Canzonieri C 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. PMID: 23722869. Giordano P et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. 2006; 4(6):1237-45. PMID: 16706966. Kjeldsen AD et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med. 2005; 258(4):349-55. PMID: 16164574. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014; 59(1):37-41. PMID: 24196379. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004; 23(4):289-99. PMID: 15024723. Machado RD et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S32-42. PMID: 19555857. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007; 52(10):820-9. PMID: 17786384. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005; 25(6):595. PMID: 15880681.
Fulgent Genetics, Fulgent Genetics	RCV000472148	SCV000893304	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755781	SCV001247162	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000472148	SCV002503656	pathogenic	Telangiectasia, hereditary hemorrhagic, type 2	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 144 in exon 4 (of 10) of ACVRL1 (p.(Arg144*)). It is expected to result in nonsense mediated decay, and loss of function is well-established mechanism of disease for this gene (ClinVar). The variant is present in a single individual in a large population cohort (1/246,414 alleles in gnomAD v2.1 and absent in gnomAD v3.1), which is consistent with dominant condition. The variant is a recurrent mutation that has been identified in multiple cases with a clinical diagnosis of hereditary haemorrhagic telangiectasia and segregates with disease in at least one four-generation family (PMID: 12700602, 15024723, 15880681, 16429404, 23722869). It has also been identified in at least one individual with idiopathic pulmonary arterial hypertension (PMID: 19555857). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PP1_Strong, PM2_Supporting.
Ambry Genetics	RCV002327029	SCV002632926	pathogenic	Cardiovascular phenotype	2022-09-14	criteria provided, single submitter	clinical testing	The p.R144* pathogenic mutation (also known as c.430C>T), located in coding exon 3 of the ACVRL1 gene, results from a C to T substitution at nucleotide position 430. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was first described in an individual with epistaxis, telangiectasias, and a family history of hereditary hemorrhagic telangiectasia (HHT) (Abdalla SA et al. Eur. J. Hum. Genet., 2003 Apr;11:279-87). This mutation has also been described in several French HHT families (Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99). Other studies identified this mutation in two individuals with multiple telangiectasias in the gastrointestinal tract, epistaxis, and pulmonary arteriovenous malformations (Canzonieri C et al. Genet Med. 2014;16(1):3-10; Verhelst X et al. Case Rep Gastroenterol Jan;12:13-18). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000755781	SCV004226857	pathogenic	not provided	2022-10-11	criteria provided, single submitter	clinical testing	PM2_supporting, PS4_moderate, PVS1
Rare Disease Genomics Group, St George's University of London	RCV000488769	SCV000576317	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only