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ADAMTS3 encodes a metalloprotease essential for VEGF-C activation in lymphangiogenesis. Hennekam lymphangiectasia-lymphedema syndrome 3 is a rare autosomal recessive disorder characterized by lymphatic dysplasia and intestinal lymphangiectasia (HP:0002593). A recent in silico analysis of 919 nsSNPs in ADAMTS3 identified 50 predicted deleterious variants, among which c.892G>C (p.Gly298Arg) was highlighted for its destabilizing impact on protein secondary structure (PMID:37322437). No clinical probands or segregation data have been reported to date, and functional evidence remains limited to computational modelling. Thus, the gene–disease association is classified as Limited, with both genetic and experimental tiers rated Limited due to absence of patient‐based or in vitro/in vivo validation.
Key take-home: Computational predictions nominate ADAMTS3 variants such as p.Gly298Arg for diagnostic screening in HKLLS3, but clinical and functional validation is required.
Gene–Disease AssociationLimitedEvidence derives solely from computational predictions without clinical probands or segregation data Genetic EvidenceLimitedNo reported patient cases or familial segregation; only in silico variant prioritization Functional EvidenceLimitedFunctional impact inferred only from molecular dynamics and stability modelling |