ClinVar Genomic variation as it relates to human health

The p.Cys344Tyr substitutes the cysteine with tyrosine at position 344 of the protein. This variant has previously been reported as pathogenic in a clinically affected individual with HHT (PMID: 10767348; see patient H167). This variant has also been reported in two individuals with adult-onset pulmonary arterial hypertension (PAH); one with PAH related to HHT (PMID: 29631995; see patient FPPH110 and FPPH139-01). Further supporting pathogenicity, different missense changes at the same amino acid residue (p.Cys344Arg, p.Cys344Phe) have been reported as pathogenic (PMID: 19767588, PMID: 12114496 and others). The p.Cys344Tyr has not been documented in large population cohorts (0 of 246,970 alleles; Genome Aggregation Database v2.1). This is an evolutionary conserved amino acid and in silico tools predict this variant has a damaging effect.

The heterozygous missense variant c.1031G>A (p.Cys344Tyr) identified in the ACVRL1 gene is a well-known pathogenic variant that has been reported in multiple unrelated individuals and families affected with HHT2 [PMID: 10767348, 14684682, 15880681, 16540754, 16542389, 17384219, 12114496]. The variant is absent from the gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant has been reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID: 8254). This variant affects a highly conserved residue (Cys344)located in the protein kinase domain of ACVRL1 and is predicted deleterious by multiple in silico prediction tools (CADD score = 34.0, REVEL score = 0.929). In vitro functional studies have shown that the p.Cys344Tyr variant results in abnormal ACVRL1 trafficking [PMID: 14684682, 16282348]. Based on the available evidence, the heterozygous c.1031G>A (p.Cys344Tyr) variant identified in the ACVRL1 gene is reported as Pathogenic.

This mutation has been described in the literature as disease-causing and has been identified once in our laboratory in an individual with HHT; the affected parent was unavailable for testing.

PP1_moderate, PP3, PM1, PM2_supporting, PM5, PS3, PS4

The ACVRL1 c.1031G>A; p.Cys344Tyr variant (rs28936688) has been reported in several individuals with HHT (Abdalla 2000, Bayrak-Toydemir 2004, Gedge 2007, Harrison 2003, Schulte 2005, Wehner 2006). This variant is also reported in ClinVar (Variation ID: 8254). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is pathogenic (REVEL: 0.929). Based on available information, this variant is considered to be pathogenic. References: Abdalla SA et al. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum Mol Genet. 2000 May 1;9(8):1227-37. PMID: 10767348. Bayrak-Toydemir P et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004 Jul-Aug;6(4):175-91. PMID: 15266205. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. PMID: 17384219. Harrison RE 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 Dec;40(12):865-71. PMID: 14684682. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. PMID: 15880681. Wehner LE et al. Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin Genet. 2006 Mar;69(3):239-45. PMID: 16542389.

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 344 of the ACVRL1 protein (p.Cys344Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 10767348, 12114496, 14684682, 15880681, 16540754, 16542389, 17384219). ClinVar contains an entry for this variant (Variation ID: 8254). 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: 14684682, 16282348). For these reasons, this variant has been classified as Pathogenic.

The p.C344Y pathogenic mutation (also known as c.1031G>A), located in coding exon 6 of the ACVRL1 gene, results from a G to A substitution at nucleotide position 1031. The cysteine at codon 344 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation has been identified in multiple unrelated patients with hereditary hemorrhagic telangiectasia (Abdalla SA et al. Hum. Mol. Genet., 2000 May;9:1227-37; Harrison RE et al. J. Med. Genet., 2003 Dec;40:865-71; Schulte C et al. Hum. Mutat., 2005 Jun;25:595; Wehner LE et al. Clin. Genet., 2006 Mar;69:239-45; Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77). ln vitro functional studies demonstrated this mutation had a dominant-negative effect on the normal protein and had reduced protein expression on the cell surface (Gu Y et al. Blood, 2006 Mar;107:1951-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that p.(C344Y) imparts a dominant-negative effect by suppressing the activity of wild-type ACVRL1 (PMID: 16282348); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (p.(C344R) and p.(C344F)) have been reported in association with a ACVRL1-related phenotype in the published literature (PMID: 23124896, 12114496); This variant is associated with the following publications: (PMID: 14684682, 16470787, 17384219, 16542389, 17786384, 25970827, 15880681, 10767348, 12114496, 16540754, 29631995, 32503579, 32300199, 23124896, 16282348)