ClinVar Miner

Submissions for variant NM_004444.5(EPHB4):c.410A>T (p.Lys137Met)

dbSNP: rs1813296662
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV002225224 SCV002503814 likely pathogenic Capillary malformation-arteriovenous malformation 2 2022-03-03 criteria provided, single submitter clinical testing This sequence change in EPHB4 is predicted to replace lysine with methionine at codon 137, p.(Lys137Met). The lysine residue is highly conserved (100 vertebrates, UCSC), and is located in the ephrin receptor ligand binding domain. There is a moderate physicochemical difference between lysine and methionine. This variant also falls at the 410 nucleotide of exon 3 of the EPHB4 coding sequence, which is part of the consensus donor splice site for this exon. This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with EPHB4-related disease. The variant is present in a single proband with a clinical diagnosis of capillary malformation-arteriovenous malformation (Royal Melbourne Hospital). Multiple lines of computational evidence predict a impact on splicing (SpliceAI, MaxEntScan, NNSplice), and predict a deleterious effect for the missense substitution (3/4 algorithms). This prediction is confirmed by RT-PCR mRNA studies in a patient with the variant. The assay demonstrated that the variant impacts splicing by predominantly producing activation of a cryptic donor within intron 3 (r.411_412ins[411+1_411+36], p.Lys137delinsMVPGCPQGSATAK). Mis-spliced transcripts are predicted to translated into an abnormal epinephrin receptor ligand binding domain, containing multiple ectopic amino acids. Increased intron 3 retention (r.411_412ins[411+1_412-1], p.Asp139Profs*27) was also detected (Splicing Diagnostics Kid's Neuroscience Centre). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS3, PS4_Supporting, PM2_Supporting, PP3.

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