ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1436G>A (p.Arg479Gln) (rs1085307426)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000546029 SCV000602430 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-12-17 criteria provided, single submitter clinical testing The ACVRL1 c.1436G>A;p.Arg479Gln variant has been described in families and individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) and has been described as segregating with disease (Bayrak-Toydemir 2006, Bayrak-Toydemir 2008, Fujiwara 2008, Gedge 2007, Lesca 2006, McDonald 2011). It is reported as pathogenic in ClinVar (Variation ID: 426035) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 479 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is deleterious. Additionally, this variant has been shown to have reduced function (Ricard 2010). Based on available information, this variant is considered pathogenic. REFERENCES Bayrak-Toydemir P et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006 Mar 1;140(5):463-70. Bayrak-Toydemir P et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008 Aug;85(1):45-9.. Fujiwara M et al. Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J. 2008 Jan;72(1):127-33. 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. Lesca G et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006 Jun;27(6):598. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Ricard N et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010 Sep 2;116(9):1604-12.
Invitae RCV000546029 SCV000639396 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-03-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 479 of the ACVRL1 protein (p.Arg479Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several unrelated individuals and families affected with hemorrhagic telangiectasia (PMID: 16470787, 16705692, 21158752, Invitae database). ClinVar contains an entry for this variant (Variation ID: 426035). Experimental studies have shown that this missense change causes lack of response to BMP9 stimulation (PMID: 20501893). For these reasons, this variant has been classified as Pathogenic.
Medical & Molecular Genetics Group,University of Lincoln RCV000488513 SCV000576344 pathogenic Primary pulmonary hypertension 1 no assertion criteria provided literature only

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