CCM2 scaffold protein (CCM2) was first reported in relation to autosomal dominant cerebral cavernous malformation 2 in 2003 (Liquori et al., PMID: 14624391). Germline variation in CCM2 accounts for approximately 20% of familial cerebral cavernous malformations (CCM) and is associated with less severe disease (PMID 39740786). CCM2 related CCMs are typically adult-onset but there is at least one reported case of onset in childhood (PMID 31937560). 20 variants (6 missense, 4 nonsense, 6 frameshift, and 4 splice site) that have been reported in 24 probands in 4 publications (PMIDs 14624391, 39181174, 31937560, 14740320) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be a two-hit mechanism, with a germline LOF variant and somatic variation in the wildtype allele at the site of lesion formation (PMIDs 19088123, 31446422). This gene-disease relationship is also supported by coimmunoprecipitation data and animal models (PMIDs 18981891, 17900104, 21596842). Experimental data confirm that CCM2 interacts with KRIT1, and PDCD10 which are both associated with monogenic CCM. Further, two mouse models support the two-hit mechanism of pathogenesis. In summary, there is definitive evidence supporting the relationship between CCM2 and autosomal dominant cerebral cavernous malformation 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Neurovascular Disorders GCEP on May 27, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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