Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clinical Genomics Laboratory, |
RCV003449821 | SCV004176952 | pathogenic | Multiple cutaneous and mucosal venous malformations | 2023-08-11 | criteria provided, single submitter | clinical testing | The TEK c.3324T>A (p.Tyr1108Ter) variant was identified at an allelic fraction consistent with somatic origin. The TEK c.3324T>A (p.Tyr1108Ter) variant has been reported in one case of venous malformation (Paolacci S et al., PMID: 33105631). Another nucleotide change, c.3342T>C, that results in the same same impact on the gene product (p.Tyr1108Ter), has been previously observed by our laboratory in an individual with vascular malformation and overgrowth. Similarly, a termination codon at this position resulting from different nucleotide changes (c.3323_3324del; c.3319_3320 del; c.3324T>C), has been reported in one individual affected with blue rubber bleb nevus syndrome and at least two individuals with venous malformations (Soblet J et al., PMID: 27519652; Mattassi R et al., PMID: 28655553; Paolacci S et al., PMID: 33105631; Sterba M et al., PMID: 37380669). The TEK c.3324T>A (p.Tyr1108Ter) variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The TEK c.3324T>A (p.Tyr1108Ter) variant causes a premature termination codon; however, because this occurs in the last exon, it is not predicted to lead to nonsense-mediated decay. This variant resides within the C-terminal tail, amino acids A905-A1124, of TEK, which is a critical functional domain (Shewchuk LM et al., PMID: 11080633). In particular, functional studies show that the C-terminal tail exerts an autoinhibitory effect on TIE2, and truncated protein products disrupting this region have been shown to increase kinase activity in vitro as well as increase downstream signaling and impair apoptosis in a cell line (Wouters V et al., PMID: 19888299; Murray BW et al., PMID: 11513602; Niu XL et al., PMID: 12082108). Furthermore, truncating variants have been reported in this region in multiple patients with vascular malformations (Soblet J et al., PMID: 23801934; Soblet J et al., PMID: 27519652; Paolacci S et al., PMID: 33105631; Sterba M et al., PMID: 37380669). 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.3324T>A (p.Tyr1108Ter) variant is classified as pathogenic. |
| MAGI's Lab - |
RCV001327976 | SCV001437652 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation |