ClinVar Miner

Submissions for variant NM_000020.2(ACVRL1):c.706G>A (p.Glu236Lys) (rs1592223490)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000814495 SCV000954908 pathogenic Telangiectasia, hereditary hemorrhagic, type 2 2020-03-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 236 of the ACVRL1 protein (p.Glu236Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hereditary hemorrhagic telangiectasia (HHT) and observed to segregate with HHT in one family (PMID: 25970827, Invitae). ClinVar contains an entry for this variant (Variation ID: 657805). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACVRL1 protein function. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000814495 SCV001473784 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2019-12-14 criteria provided, single submitter clinical testing The ACVRL1 c.706G>A; p.Glu236Lys variant is reported in the literature in at least one family affected with hereditary hemorrhagic telangiectasia (Heimdal 2016). This variant is reported in ClinVar (Variation ID: 657805), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 236 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Glu236Lys variant is uncertain at this time. References: Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6.
Mayo Clinic Laboratories, Mayo Clinic RCV001507806 SCV001713599 likely pathogenic not provided 2021-02-18 criteria provided, single submitter clinical testing PS4_moderate, PM2-supporting, PP4, PP3, PS3_supporting, PP1

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