ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1121G>A (p.Arg374Gln) (rs1060503248)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467491 SCV000552416 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-03-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 374 of the ACVRL1 protein (p.Arg374Gln). 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 individuals affected with hereditary hemorrhagic telangiectasia and has been described to segregate with the disease in at least one family (PMID: 12700602, 18285823, 21158752, 25970827). ClinVar contains an entry for this variant (Variation ID: 411314). A different missense substitution at this codon (p.Arg374Trp) has been determined to be pathogenic (PMID: 12700602, 15517393, 17384219, 20501893). This suggests that the arginine residue is critical for ACVRL1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change reduces ACVRL1 kinase activity (PMID: 20501893). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000467491 SCV000602407 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-04-06 criteria provided, single submitter clinical testing The ACVRL1 c.1121G>A; p.Arg374Gln variant (rs1060503248) has been reported in the literature in individuals with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arterial hypertension (PAH) (Abdalla 2003, Harrison 2003, McDonald 2011, Yang 2018), and has been shown to have defective BMP9 ligand signaling (Ricard 2010). This variant has been reported in ClinVar (Variation ID: 411314) and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 374 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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 Apr;11(4):279-87. 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. 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. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87.
Medical & Molecular Genetics Group,University of Lincoln RCV000488746 SCV000576331 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia no assertion criteria provided literature only
GeneDx RCV001576840 SCV001804103 pathogenic not provided 2019-09-20 no assertion criteria provided clinical testing R374Q has been shown to segregate with HHT in at least two affected relatives from two families (Abdalla et al., 2003; Chen et al., 2013); Published functional studies in transfected cultured cells suggest that although ACVRL1 receptors harboring R374Q can bind BMP9 ligand at the cell surface, the BMP9 signaling response is impaired (Ricard et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12700602, 29743074, 20501893, 32300199, 21158752, 14684682, 25970827, 23919827, 18673552, 17384219, 18285823, 17786384, 15517393, 31511490)

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