ClinVar Miner

Submissions for variant NM_002401.5(MAP3K3):c.1323C>G (p.Ile441Met)

dbSNP: rs2143631386
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV002254484 SCV002525689 pathogenic Verrucous hemangioma 2021-01-12 criteria provided, single submitter clinical testing This variant has previously been reported in affected tissues in 6/10 individuals with verrucous venous malformations (PMID: 25728774). The variant has not been reported in large population studies (Genome Aggregation Database v2.1.1). To date, no somatic mutation affecting p.Ile441 has been reported in COSMIC, the catalog of somatic mutation in cancer, nor the NCI Genomic Data Commons database.
Clinical Genomics Laboratory, Washington University in St. Louis RCV003458852 SCV004176900 likely pathogenic Verrucous venous malformation 2023-08-27 criteria provided, single submitter clinical testing The MAP3K3 c.1323C>G (p.Ile441Met) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in nine individuals affected with cerebral cavernous malformations (CCMs) (Weng J et al., PMID: 33891857; Ren J et al., PMID: 36917268) and three individuals affected with verrucous venous malformation (Couto JA et al., PMID: 25728774). MAP3K3 c.1323C>G (p.Ile441Met) has been reported in the ClinVar database as pathogenic by one submitter (ClinVar ID: 1691386). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies using animal models generated with this variant expressed intracranial lesions that resemble human CCMs (Ren J et al., PMID: 36917268). Furthermore, studies using animals and cell lines demonstrated hyperactivation of downstream signaling pathway (Weng J et al., PMID: 33891857; Huo R et al., PMID: 36090889). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), MAP3K3 c.1323C>G (p.Ile441Met) variant is classified as likely pathogenic
OMIM RCV004799648 SCV005420916 pathogenic CEREBRAL CAVERNOUS MALFORMATIONS 5, SOMATIC 2024-12-06 no assertion criteria provided literature only

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