ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.682G>A (p.Val228Ile) (rs138048445)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198425 SCV000249629 likely pathogenic not provided 2015-06-04 criteria provided, single submitter clinical testing p.Val228Ile (GTC>ATC): c.682 G>A in exon 6 in the ACVRL1 Gene (NM_000020.2). The V228I variant in the ACVRL1 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V228I variant was not observed with a significant frequency 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 V228I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense mutation at the same residue (V228D) has been reported in association with HHT, supporting the functional importance of this residue in the protein. The V228I variant is a strong candidate for a disease-causing mutation, however the possibility it may be a rare benign variant cannot be excluded. This variant has been observed to be maternally inherited with confirmed parentage with an apparently unaffected mother. This variant was found in HG19-REANALYSIS panel(s).

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