ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.1219G>A (p.Glu407Lys) (rs1057521203)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756964 SCV000884969 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000756964 SCV000521599 uncertain significance not provided 2015-12-03 criteria provided, single submitter clinical testing A novel variant of uncertain significance has been identified in the ACVRL1 gene. The E407K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, two different missense changes affecting the same amino acid residue (E407D, E407G) have been reported in the literature in association with HHT (Gedge et al., 2007; Bayrak-Toydemir et al., 2008; Abdalla et al., 2000; Abdalla et al., 2003; Kuehl et al., 2005; Olivieri et al., 2007; Brakensiek et al., 2008; Canzonieri et al., 2014). Bayrak-Toydemir et al. (2008) reported E407G in a proband with HHT and in four affected family members; it was absent from 200 control alleles. Two additional affected family members were not tested for the variant but were obligate carriers (Bayrak-Toydemir et al., 2008). Abdalla et al. (2003) described the E407D variant in a 57-year-old man who had recurrent epistasis and severe GI bleeding and in his 28-year-old daughter who had recurrent epistaxis; his 31 year-old son also had recurrent epistaxis but declined genetic testing. Canzonieri et al. (2014) identified E407D in a 59-year-old male with epistaxis, hepatic AVMs, and telangiectases in the stomach and duodenum.The E407K variant 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. The E407K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Several missense variants in nearby residues (G402S, G402D, L403P, W406C, R411W, R411P, R411Q) have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014), further supporting the functional importance of this region of the protein. However, additional evidence is needed to determine whether this variant is pathogenic or benign.

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