Submissions for variant NM_000459.5(TEK):c.3323_3324insCGTGAATACCACGCTTTATGAGAAGTAGTA (p.Tyr1108_Glu1109insValAsnThrThrLeuTyrGluLysTer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004566492	SCV005049520	likely pathogenic	Multiple cutaneous and mucosal venous malformations	2024-03-06	criteria provided, single submitter	clinical testing	A TEK c.3323_3324insCGTGAATACCACGCTTTATGAGAAGTAGTA (p.Tyr1108_Glu1109insValAsnThrThrLeuTyrGluLys*) variant was identified at an allelic fraction consistent with somatic origin. This variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.4.0.0), indicating it is not a common variant. This variant is an insertion of 30 base pairs resulting in a premature termination codon, however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. Functional studies have demonstrated that other variants within this region result in the truncation of the C-terminal inhibitory loop, leading to increased receptor autophosphorylation (Boscolo E et al., PMID: 26258417; Soblet J et al., PMID: 23801934). Furthermore, numerous other insertion/deletion variants have been reported in this region in multiple patients with vascular/venous malformations (ClinVar). Based on an internally-developed protocol informed by the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), and gene-specific practices from the ClinGen Criteria Specification Registry, the TEK c.3323_3324insCGTGAATACCACGCTTTATGAGAAGTAGTA (p.Tyr1108_Glu1109insValAsnThrThrLeuTyrGluLys*) variant is classified as likely pathogenic.