ClinVar Miner

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

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Total submissions: 2
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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).
Invitae RCV001340965 SCV001534800 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2020-07-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 228 of the ACVRL1 protein (p.Val228Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs138048445, ExAC 0.01%). This variant has been observed in individual(s) with pulmonary arterial hypertension (PMID: 27630060). ClinVar contains an entry for this variant (Variation ID: 212799). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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