ClinVar Miner

Submissions for variant NM_004444.5(EPHB4):c.1190G>A (p.Arg397His)

gnomAD frequency: 0.00003  dbSNP: rs538766032
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Goettingen RCV002261471 SCV002540758 uncertain significance Capillary malformation-arteriovenous malformation 2 2022-07-07 criteria provided, single submitter clinical testing The variant c.1190G>A (p.(Arg397His)) in exon 6 of the EPHB4-gene is found at a population frequency of 0.0035% in the gnomAD database, it affects a weakly conserved nucleotide, a moderately conserved amino acid within a protein domain and there is a small physicochemical difference between Arg and His. ACMG criteria used for classification: PM2.
Molecular Genetics, Royal Melbourne Hospital RCV002261471 SCV004812367 uncertain significance Capillary malformation-arteriovenous malformation 2 2022-10-06 criteria provided, single submitter clinical testing This sequence change in EPHB4 is predicted to replace arginine with histidine at codon 397, p.(Arg397His). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in fibronectin type-III domain 1. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.008% (3/35,422 alleles) in the Latino/admixed American population. To our knowledge, this variant has not been reported in the literature in any individuals with EPHB4-related disease. This variant has been reported in at least one proband with macular telangiectasia (ClinVar: SCV002540758.1). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
Ambry Genetics RCV004990755 SCV005577665 likely benign Cardiovascular phenotype 2024-08-03 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV005095917 SCV005730413 likely benign not provided 2024-12-05 criteria provided, single submitter clinical testing

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