Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
SIB Swiss Institute of Bioinformatics | RCV000852308 | SCV000994941 | likely pathogenic | Capillary malformation-arteriovenous malformation 2 | 2019-03-29 | criteria provided, single submitter | curation | This variant is interpreted as a Likely pathogenic for Capillary malformation-arteriovenous malformation 2. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g.,active site of an enzyme) without benign variation. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3: Well-established functional studies show a deleterious effect. |
ARUP Laboratories, |
RCV001002591 | SCV001160564 | likely pathogenic | not specified | 2019-05-23 | criteria provided, single submitter | clinical testing | The EPHB4 c.2533T>C; p.Cys845Arg variant is reported in the literature in an individual with capillary malformation-arteriovenous malformation (CM-AVM) and functional analyses show this variant leads to proteosomal degradation of the protein (Amyere 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 845 is highly a highly conserved residue in the protein kinase domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Amyere M et al. Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation. 2017 Sep 12;136(11):1037-1048. |