ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.772G>A (p.Gly258Ser) (rs1555152966)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetics,Medical University of Vienna RCV000513504 SCV000346041 likely pathogenic Osler hemorrhagic telangiectasia syndrome no assertion criteria provided clinical testing
Invitae RCV000694605 SCV000823056 uncertain significance Hereditary hemorrhagic telangiectasia type 2 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 258 of the ACVRL1 protein (p.Gly258Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 6 of the ACVRL1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hereditary hemorrhagic telangiectasia (PMID: 20414677). ClinVar contains an entry for this variant (Variation ID: 444101). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

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