Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| SIB Swiss Institute of Bioinformatics | RCV000852311 | SCV000994946 | 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. |
| Invitae | RCV003718303 | SCV004509254 | uncertain significance | not provided | 2023-03-30 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 867 of the EPHB4 protein (p.Phe867Leu). This missense change has been observed in individual(s) with clinical features of autosomal dominant capillary malformation-arteriovenous malformations (PMID: 30578106; external communication). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects EPHB4 function (PMID: 30578106). 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. ClinVar contains an entry for this variant (Variation ID: 691536). |