ClinVar Miner

Submissions for variant NM_001077401.2(ACVRL1):c.1451G>A (p.Arg484Gln) (rs863223408)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198604 SCV000249626 pathogenic not provided 2015-02-18 criteria provided, single submitter clinical testing The R484Q mutation in the ACVRL1 gene has been reported previously in association with both HHT and pulmonary arterial hypertension (PAH) (Harrison R et al., 2005; Olivieri C et al., 2006; Best D et al., 2011; Pfarr N et al., 2013). Pfarr et al. (2013) reported R484Q is associated with a variable phenotype even within the same family, with one heterozygous individual affected with HHT and two heterozygous individuals affected with hereditary PAH. R484Q results in a semi-conservative amino acid substitution at a position that is highly conserved across species. Ricard N et al. (2010) report that mutations in residue 484, located in the highly conserved NANDOR box region, cause defective signaling with the BMP9 ligand. Mutations in the same residue (R484G, R484W, R484L) and in nearby residues (L480F, A482E, I485F, K486M) have been reported in association with disease, further supporting the functional importance of this residue and this region of the protein. Furthermore, the R484Q mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant was found in ACVRL1, HHT-ARRHYTHMIA panel(s).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414952 SCV000492684 pathogenic Pulmonary arterial hypertension; Epistaxis 2015-11-24 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000502469 SCV000598155 pathogenic Hereditary hemorrhagic telangiectasia type 2 2016-09-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506673 SCV000602425 pathogenic not specified 2016-12-04 criteria provided, single submitter clinical testing
Invitae RCV000502469 SCV000822890 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 484 of the ACVRL1 protein (p.Arg484Gln). 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 observed in individuals and families affected with hereditary haemorrhagic telangiectasia or pulmonary arterial hypertension (PMID:15687131, 21378382, 23298310, 18159113, 22632830, 17786384, 23919827). ClinVar contains an entry for this variant (Variation ID: 212796). Experimental studies have shown that this missense change affects protein trafficking (PMID: 20501893). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Arg484 amino acid residue in ACVRL1 have been observed in affected individuals (PMID: 20501893, 16540754, 20056902, 11484689, 27316748, 23124896, 18498373). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Medical & Molecular Genetics Group,University of Lincoln RCV000488871 SCV000576349 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia no assertion criteria provided literature only

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