ClinVar Miner

Submissions for variant NM_001077401.2(ACVRL1):c.1232G>A (p.Arg411Gln) (rs121909284)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000008726 SCV000552399 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 411 of the ACVRL1 protein (p.Arg411Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121909284, ExAC 0.01%). This variant has been reported in the literature co-segregating in a family with hereditary hemorrhagic telangiectasia (HHT) (PMID: 8640225) as well as in multiple unrelated individuals affected with HHT (PMID: 15024723, 20414677, 23805858). ClinVar contains an entry for this variant (Variation ID: 8243). Experimental studies have shown that this missense change causes a lack of response to BMP9 stimulation and protein mislocalization disrupting ACVRL1 protein function (PMID: 20501893, 14684682). Two other different missense substitution at this codon (p.Arg411Pro, p.Arg411Trp) have been determined to be pathogenic (PMID: 15024723, 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. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506300 SCV000602399 pathogenic not specified 2017-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000522363 SCV000617301 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing The R411Q pathogenic variant in the ACVRL1 gene has been reported in many times in association with HHT (Johnson et al., 1996; Berg et al., 1997; Lesca et al., 2004; Schulte et al., 2005). Johnson et al. (1996) first reported this variant in a large family with HHT and demonstrated that it segregated with disease in eight family members. Multiple functional studies have shown that R411Q results in reduced ACVRL1 activity (Gu et al., 2006; Ricard et al., 2010; Laux et al., 2013). R411Q results in a semi-conservative amino acid substitution at a position that is conserved across species. Additionally, variants in the same residue (R411W, R411P) have been reported in HGMD in association with HHT (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Furthermore, the R411Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Fulgent Genetics,Fulgent Genetics RCV000008726 SCV000893308 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-10-31 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000008726 SCV000928397 pathogenic Hereditary hemorrhagic telangiectasia type 2 2018-11-20 criteria provided, single submitter clinical testing PM1, PM5, PP2, PP3, PP4, PP5
OMIM RCV000008726 SCV000028935 pathogenic Hereditary hemorrhagic telangiectasia type 2 2004-04-01 no assertion criteria provided literature only
OMIM RCV000008727 SCV000028936 pathogenic Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia 2004-04-01 no assertion criteria provided literature only
Blueprint Genetics RCV000008726 SCV000206819 pathogenic Hereditary hemorrhagic telangiectasia type 2 2014-10-06 no assertion criteria provided clinical testing

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