Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clinical Genomics Laboratory, |
RCV003449820 | SCV004176927 | pathogenic | Multiple cutaneous and mucosal venous malformations | 2023-10-12 | criteria provided, single submitter | clinical testing | The TEK c.3295C>T (p.Arg1099Ter) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations (Soblet J et al., PMID: 23801934; Soblet J et al., PMID: 27519652; Nätynki M et al., PMID: 26319232; Paolacci S et al., PMID: 33105631). This variant is absent from the general population (gnomAD v3.1.2), indicating it is not a common variant. The TEK c.3295C>T (p.Arg1099Ter) variant causes a premature termination codon; however, because this occurs in the penultimate exon, it is not predicted to lead to nonsense-mediated decay. This 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 truncates the C-terminal inhibitory loop and causes increased receptor autophosphorylation, indicating that this variant impacts protein function (Boscolo E et al., PMID: 26258417; Soblet J et al., PMID: 23801934). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the TEK c.3295C>T (p.Arg1099Ter) variant is classified as pathogenic. |
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV003449820 | SCV005326307 | pathogenic | Multiple cutaneous and mucosal venous malformations | criteria provided, single submitter | clinical testing | The p.Arg1099* variant results in a premature stop codon within the penultimate exon (exon 22) of the TEK gene and is predicted to escape nonsense mediated decay. The p.Arg1099* variant has been reported in blue rubber bleb nevus (BRBN) syndrome and venous malformations (PMID: 27519652, PMID: 23801934). It is absent from large population databases (gnomAD v4.1.0). Late truncating mutations in TEK have been reported in individuals with sporadic venous malformations and functional studies of C-terminal mutations have been shown to lead to ligand-independent kinase activation (https://www.ncbi.nlm.nih.gov/books/NBK1967/). | |
| MAGI's Lab - |
RCV001327975 | SCV001437651 | pathogenic | Abnormal cardiovascular system morphology | no assertion criteria provided | provider interpretation |