Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| SIB Swiss Institute of Bioinformatics | RCV000852318 | SCV000994953 | 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: PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. 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. PS4-Supporting: Recurrent variant (PS4 downgraded in strength to Supporting). |
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV002254321 | SCV002525627 | pathogenic | not provided | 2020-04-28 | criteria provided, single submitter | clinical testing | This pathogenic variant has been previously reported, carried by five affected individuals from two families (PMID: 28687708). The clinical presentation of all five individuals included capillary malformations and one was reported to have Parkes Weber syndrome. This is a conserved residue across species and in silico tools predict the p.Asn745Asp change is damaging to protein function (DANN, MutationTaster, and SIFT) versus no benign predictions. |
| Invitae | RCV002254321 | SCV004294529 | likely pathogenic | not provided | 2022-12-15 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with capillary malformation-arteriovenous malformation (PMID: 28687708). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 745 of the EPHB4 protein (p.Asn745Asp). ClinVar contains an entry for this variant (Variation ID: 691543). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 EPHB4 protein function. |