ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1445C>T (p.Ala482Val) (rs139142865)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000196441 SCV000602421 benign not specified 2016-05-06 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148353 SCV000190043 likely benign Haemorrhagic telangiectasia 2 2014-06-01 no assertion criteria provided research
GeneDx RCV000766346 SCV000249625 uncertain significance not provided 2014-11-18 criteria provided, single submitter clinical testing p.Ala482Val (A482V) GCG>GTG: c.1445 C>T in exon 10 of the ACVRL1 gene (NM_000020.2). The A482V variant in the ACVRL1 gene has been reported in several unrelated individuals with HHT (Lesca G et al., 2004; Schulte C et al., 2005). However, additional publications report that the A482V variant is found in individuals with HHT when there is an additional disease causing mutation present (Letteboer T et al., 2005; McDonald J et al., 2009). Furthermore, functional studies show that the A482V variant does not alter protein function (Ricard N et al., 2010). In addition, the NHLBI Exome Sequencing Project reports A482V was observed in 25/8600 alleles (0.3%) from individuals of European ancestry, indicating it may be a rare benign variant in this population. Although this substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function, the A482V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. A missense mutation in this residue (A482E) and missense mutations in nearby residues (L480F, R484W, R484G, R484L, R484Q) have been reported in association with HHT and PAH (Olivieri C et al., 2007), supporting the functional importance of this residue and region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in HHT-PANCARD,PAH-ARRHYTHMIA panel(s).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000470977 SCV000743470 benign Hereditary hemorrhagic telangiectasia type 2 2014-10-09 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000470977 SCV000745688 likely benign Hereditary hemorrhagic telangiectasia type 2 2016-11-09 no assertion criteria provided clinical testing
Invitae RCV000470977 SCV000562552 likely benign Hereditary hemorrhagic telangiectasia type 2 2017-11-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000196441 SCV000538228 likely benign not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in multiple control cohorts; ExAC: 0.3% (190/66476) European chromosomes

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