ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.266G>T (p.Cys89Phe) (rs1060503234)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475892 SCV000552397 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2016-07-09 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 89 of the ACVRL1 protein (p.Cys89Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ACVRL1-related disease. 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. This variant affects a cysteine residue located within the ACVRL1 protein ectodomain. Cysteine residues in this domain of ACVRL1 are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 22028876, 22718755, 22799562). In addition, missense substitutions within the ACVRL1 ectodomain affecting cysteine residues are overrepresented in patients with HHT (PMID: 20501893, 26176610 and www.hhtmutation.org). In summary, this is a novel missense variant that affects a residue that is expected to have a deleterious impact on protein function. However, in the absence of any segregation or direct functional studies, at this time this change has been classified as a Variant of Uncertain Significance.

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