Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV002245906 | SCV002513184 | pathogenic | not provided | 2022-05-04 | criteria provided, single submitter | clinical testing | Also observed as a somatic alteration in two patients with cavernous hemangiomas (Zhou et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19079259, 27519652, 35181412, 34166070, 33470620, 32754818, 34698142, 34209679, 26115772) |
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV002245906 | SCV002525615 | pathogenic | not provided | 2021-06-08 | criteria provided, single submitter | clinical testing | The p.Arg915Cys substitution was described in blue rubber bleb nevus syndrome and sporadically occurring venous malformations (PMID: 27519652, PMID: 19079259, PMID: 21962923, PMID: 23801934, NBK1967). |
| Revvity Omics, |
RCV002245906 | SCV004238756 | likely pathogenic | not provided | 2023-03-31 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV005251261 | SCV005902249 | pathogenic | Vascular malformation | 2024-06-27 | criteria provided, single submitter | clinical testing | A TEK c.2743C>T (p.Arg915Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with vascular malformations (Soblet J et al., PMID: 27519652; Nozawa A et al., PMID: 36171295; McNulty SN et al., PMID: 31585106; Li D et al., PMID: 37264205) and has been reported in two cases in the cancer database COSMIC (Genomic Mutation ID: COSV66229101). This variant has been reported in the ClinVar database as pathogenic/likely pathogenic in both a somatic and a germline state (ClinVar ID: 981227). The TEK c.2743C>T (p.Arg915Cys) variant is absent from the general population (gnomAD v4.1.0), indicating it is not a common variant. This variant resides within the kinase domain of TIE2, an endothelium-specific receptor tyrosine kinase, that is a critical functional domain (Shewchuk LM et al., PMID: 11080633). Another variant in the same codon, c.2744G>A (p.Arg915His), has been reported and is considered pathogenic (ClinVar ID: 30054). Computational predictors indicate that the variant is damaging, evidence that may correlate with impact to TEK function. In support of this prediction, in vitro functional studies show that this variant induces phosphorylation of TIE2 and the downstream AKT resulting in enhanced colony formation capacities of the cells (Soblet J et al., PMID: 27519652; Natynki M et al., PMID: 26319232).Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the TEK c.2743C>T (p.Arg915Cys) variant is classified as pathogenic. |
| MAGI's Lab - |
RCV001327970 | SCV001437646 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation |