ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.955G>C (p.Gly319Arg) (rs1085307414)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000640435 SCV000762026 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-02-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 319 of the ACVRL1 protein (p.Gly319Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with pulmonary arterial hypertension or hereditary hemorrhagic telangiectasia (PMID: 26387786, 27316748, Invitae). ClinVar contains an entry for this variant (Variation ID: 426022). This variant has been reported to affect ACVRL1 protein function (PMID: 27316748). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756962 SCV000884967 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing The ACVRL1 c.955G>C; p.Gly319Arg variant (rs1085307414) has been reported in the literature in individuals with pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) (Machado 2015, Piao 2016). Functional studies show the variant protein has decreased Smad 1/5 phosphorylation, and reduced activity in a luciferase reporter assay (Piao 2016). Additionally, a different variant at this codon (p.Gly319Asp) has been reported in two individuals with HHT (Lesca 2006). The p.Gly319Arg variant is listed in the ClinVar database (Variation ID: 426022), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database). The glycine at codon 319 is a highly conserved residue in the protein kinase domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, the p.Gly319Arg variant is considered pathogenic. REFERENCES Lesca G et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006 Jun;27(6):598. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. Piao C et al. Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. Clin Sci (Lond). 2016 Sep 1;130(17):1559-69.
Medical & Molecular Genetics Group,University of Lincoln RCV000488697 SCV000576328 pathogenic Primary pulmonary hypertension 1 no assertion criteria provided literature only

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