ClinVar Miner

Submissions for variant NM_004444.5(EPHB4):c.2590C>T (p.Arg864Trp) (rs769965440)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000852326 SCV000994961 pathogenic Capillary malformation-arteriovenous malformation 2 2019-03-29 criteria provided, single submitter curation This variant is interpreted as a 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. PS3: Well-established functional studies show a deleterious effect. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS4-Supporting: Recurrent variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002544 SCV001160511 likely pathogenic not specified 2019-04-18 criteria provided, single submitter clinical testing The EPHB4 c.2590C>T; p.Arg864Trp variant (rs769965440) is reported in the literature in at least three individuals affected with capillary malformations (Amyere 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 864 is highly conserved, it occurs in the EPHB4 kinase domain (Amyere 2017), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with this, expression in cultured cells suggests the p.Arg864Trp variant is mislocalized and rapidly degraded (Amyere 2017). 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.

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