Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756767 | SCV000884675 | pathogenic | not provided | 2017-10-02 | criteria provided, single submitter | clinical testing | The p.Tyr897Cys variant has been previously reported in association with vascular malformations in 3 individuals from 3 generations (Wouters 2010). Another change of the same amino acid, Tyr897Ser has been identified in 6 individuals with vascular malformations from three generations (Calvert 1999). Furthermore, in vitro functional studies performed by Wouters et al. demonstrated that the p.Tyr897Cys change greatly increases ligand independent phosphorylation in a manner similar to other pathogenic variants. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the genome Aggregation Database (gnomAD) browser. Based on these observations the p.Tyr897Cys variant has been classified pathogenic. |
| Clinical Genomics Laboratory, |
RCV000022955 | SCV004176926 | pathogenic | Multiple cutaneous and mucosal venous malformations | 2023-10-12 | criteria provided, single submitter | clinical testing | The TEK c.2690A>G (p.Tyr897Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations (Ten Broek RW et al., PMID: 30677207; Soblet J et al., PMID: 23801934; Wouters V et al., PMID: 19888299; Limaye N et al., PMID: 19079259; Zhou M et al., PMID: 26115772; Ye C et al., PMID: 21962923) and Blue Rubber Bleb Nevus (BRBN) Syndrome (Soblet J et al., PMID: 27519652). This variant has been reported in the ClinVar database as a pathogenic variant (ClinVar ID: 30053). This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. The TEK c.2690A>G (p.Tyr897Cys) variant resides within the cytoplasmic kinase domain of TEK, which is a critical functional domain (Shewchuk LM et al., PMID: 11080633). Functional studies show that this variant increases ligand-independent receptor phosphorylation as compared with the wild-type receptor, an effect that is compounded in the presence of double variants (Limaye N et al., PMID: 19079259, Nätynki M et al., PMID: 26319232; Wouters V et al., PMID: 19888299). 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), the TEK c.2690A>G (p.Tyr897Cys) variant is classified as pathogenic. |
| OMIM | RCV000022955 | SCV000044246 | pathogenic | Multiple cutaneous and mucosal venous malformations | 2010-04-01 | no assertion criteria provided | literature only | |
| MAGI's Lab - |
RCV001327971 | SCV001437647 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation |