ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.998G>T (p.Ser333Ile) (rs863223413)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198205 SCV000249632 pathogenic not provided 2014-06-11 criteria provided, single submitter clinical testing The S333I mutation in the ACVRL1 gene has been reported previously in several unrelated patients with HHT (Berg J et al., 1997; Lux A et al., 2013). Functional studies of the S333I mutation showed a dominant-negative effect and suppressed normal ACVRL1 protein activity (Abdalla S et al., 2000; Gu Y et al 2006). The S333I mutation 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 S333I mutation 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 completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a mutation in this residue (S333G) and mutations in nearby residues (D330N, D330Y, F331S, N335H) have been reported in association with HHT, further supporting the functional importance of this residue and region of the protein. This variant was found in ACVRL1,HHT-ARRHYTHMIA panel(s).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000198205 SCV000602408 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762899 SCV000893306 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000762899 SCV001588946 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 333 of the ACVRL1 protein (p.Ser333Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary hemmorhagic telangiectasia (PMID: 21158752, 12843319, 10767348, 9245985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212802). This variant has been reported to affect ACVRL1 protein function (PMID: 16282348). For these reasons, this variant has been classified as Pathogenic.

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