Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| SIB Swiss Institute of Bioinformatics | RCV000722061 | SCV000994945 | 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: 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. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3: Well-established functional studies show a deleterious effect. |
| Rady Children's Institute for Genomic Medicine, |
RCV004547917 | SCV004046389 | pathogenic | EPHB4-related disorder | criteria provided, single submitter | clinical testing | This variant has been previously reported in affected individuals from a single family with features of capillary malformation-arteriovenous malformation-2 (MIM: #618196; PMID: 28687708). In vitro functional studies performed on COS7 cells support a loss-of-function effect for the c.1990G>A (p.Glu664Lys) variant (PMID: 28687708). This variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Analysis of the similarly affected sibling sample was heterozygous for the variant. Based on the available evidence, the c.1990G>A (p.Glu664Lys) variant is classified as Pathogenic. | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000722061 | SCV004223661 | likely pathogenic | Capillary malformation-arteriovenous malformation 2 | 2023-11-10 | criteria provided, single submitter | clinical testing | Variant summary: EPHB4 c.1990G>A (p.Glu664Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251450 control chromosomes. c.1990G>A has been reported in the literature in at-least three individuals from one family affected with Capillary Malformation (example, Amyere_2017). These data indicate that the variant may be associated with Capillary Malformation-Arteriovenous Malformation 2. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of EPHB4 in COS7 cells (Amyere_2017). The following publication have been ascertained in the context of this evaluation (PMID: 28687708). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic, n=1; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Gene |
RCV004719973 | SCV005326252 | likely pathogenic | not provided | 2024-02-02 | criteria provided, single submitter | clinical testing | Observed in a cohort of patients with capillary malformation-arteriovenous malformation (CM-AVM) syndrome (PMID: 28687708); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect due to reduced protein expression (PMID: 28687708); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30819650, 28687708) |
| OMIM | RCV000722061 | SCV000853241 | pathogenic | Capillary malformation-arteriovenous malformation 2 | 2018-11-26 | no assertion criteria provided | literature only |