Submissions for variant NM_004444.5(EPHB4):c.2512C>T (p.Arg838Trp)

gnomAD frequency: 0.00001  dbSNP: rs764827256

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000852325	SCV000994960	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: 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.
CeGaT Center for Human Genetics Tuebingen	RCV001092660	SCV001249271	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000852325	SCV001736720	likely pathogenic	Capillary malformation-arteriovenous malformation 2	2021-04-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001092660	SCV002049002	likely pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing	The EPHB4 c.2512C>T; p.Arg838Trp variant (rs764827256) is reported in the literature in one individual affected with capillary malformation (Amyere 2017). Functional analyses of the variant protein in cell lines show low protein levels, likely caused by lysosomal degradation (Amyere 2017). This variant is also reported in ClinVar (Variation ID: 691550). This variant is found in the general population with an overall allele frequency of 0.0014% (3/216,384 alleles) in the Genome Aggregation Database. The arginine at codon 838 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.898). Based on available information, this variant is considered to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092660	SCV002175377	uncertain significance	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 838 of the EPHB4 protein (p.Arg838Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with EPHB4-related conditions (PMID: 28687708). ClinVar contains an entry for this variant (Variation ID: 691550). 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. Experimental studies have shown that this missense change affects EPHB4 function (PMID: 28687708). 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.