Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
ARUP Laboratories, |
RCV001810558 | SCV001474176 | pathogenic | not provided | 2020-02-21 | criteria provided, single submitter | clinical testing | The EPHB4 c.1423-6G>A variant (rs762817852) is reported in the literature in individuals affected with capillary malformation-arteriovenous malformation 2, including one de novo occurence (Amyere 2017, Wooderchak-Donahue 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Functional analyses demonstrate mRNA with an insertion of 4 nucleotides of intronic sequence resulting in a frameshift (p.Gly475Thrfs*39) (Amyere 2017). Based on available information, this variant is considered to be 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. Wooderchak-Donahue WL et al. Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genet Med. 2019 Sep;21(9):2007-2014. |
Centre de Biologie Pathologie Génétique, |
RCV002274179 | SCV002558899 | likely pathogenic | Hereditary lymphedema type I | criteria provided, single submitter | clinical testing | ||
Labcorp Genetics |
RCV001810558 | SCV003440087 | likely pathogenic | not provided | 2023-12-28 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the EPHB4 gene. It does not directly change the encoded amino acid sequence of the EPHB4 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of EPHB4-related conditions (PMID: 28687708, 30760892). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 994305). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
Clinical Genetics Laboratory, |
RCV001810558 | SCV005197830 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing |