Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000519290 | SCV000621729 | uncertain significance | not provided | 2017-10-20 | criteria provided, single submitter | clinical testing | The R918H variant in the TEK gene has been previously reported as a somatic variant in vascular malformations, but has not been reported in the germline (Ye et al., 2011). A different missense variant at the same residue, R918C, has been identified in a family with hereditary cutaneomucosal venous malformations (Wouters et al., 2010). The R918H variant is not observed in large population cohorts (Lek et al., 2016). The R918H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position with the protein kinase domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R918H as a variant of uncertain significance. |
| Institute of Medical and Molecular Genetics, |
RCV001706660 | SCV001934200 | likely pathogenic | Segmental undergrowth associated with venous malformation without capillary component | 2021-04-06 | criteria provided, single submitter | clinical testing | |
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV000519290 | SCV002525613 | uncertain significance | not provided | 2021-04-23 | criteria provided, single submitter | clinical testing | The p.Arg918His substitution was described in a single patient (case #30, PMID: 33105631) with venous malformation. |
| Clinical Genomics Laboratory, |
RCV003458451 | SCV004176904 | likely pathogenic | Vascular malformation | 2023-09-06 | criteria provided, single submitter | clinical testing | The TEK c.2753G>A (p.Arg918His) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals with venous malformations and Blue Rubber Bleb Nevus Syndrome (Limaye N et al., PMID: 26637981; Ye C et al., PMID: 21962923; Paolacci S et al., PMID: 33105631; Soblet J et al., PMID: 27519652). This variant has been reported in the ClinVar database as a likely pathogenic somatic variant by one submitter (ClinVar ID: 452884). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Another variant in the same codon, c.2752C>T (p.Arg918Cys), has been reported in multiple individuals affected with venous malformations (Ten Broek RW et al., PMID: 30677207; Limaye N et al., PMID: 26637981; Ye C et al., PMID: 21962923; Soblet J et al., PMID: 23801934; Paolacci S et al., PMID: 33105631; Soblet J et al., PMID: 27519652; ClinVar Variation ID: 981228). The TEK c.2753G>A (p.Arg918His) variant resides within a catalytic domain of the protein Tyrosine Kinase, Tie2, A816-A1118, of TEK that is defined as a critical functional domain (Shewchuk LM et al., PMID: 11080633). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on TEK function. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the TEK c.2753G>A (p.Arg918His) variant is classified as likely pathogenic. |
| MAGI's Lab - |
RCV001327974 | SCV001437650 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation |