Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Familial cerebral cavernous malformation (FCCM) is an autosomal dominant vascular disorder characterized by multifocal, thin-walled vascular lesions in the central nervous system with incomplete penetrance and variable clinical expressivity. Germline heterozygous mutations in the CCM2 gene (malcavernin) disrupt the formation of the CCM1/CCM2/CCM3 trimeric complex and underlie FCCM pathogenesis ([PMID:30701383]). Clinical presentation often includes headache, seizures (HP:0001250), or incidental findings on neuroimaging.
In a Chinese family, the nonsense variant c.55C>T (p.Arg19Ter) segregated with FCCM in the proband and four affected relatives, while a noncoding variant c.*18G>A was also identified ([PMID:30701383]). A larger Italian single-center study of 317 CCM index cases found loss-of-function CCM2 variants in eight probands, with segregation confirmed in 60 additional mutation-positive relatives ([PMID:30161288]). This demonstrates clear familial segregation consistent with haploinsufficiency.
In the Brain Vascular Malformation Consortium cohort, CCM2 mutations accounted for 5% of pathogenic alleles among 393 genotyped FCCM cases, with earlier age at seizure onset correlating with total lesion burden but not specifically with CCM2 genotype ([PMID:34389651]). Radiologic analysis further implicated CCM2 variants in higher frequency of brainstem lesions and age-related lesion progression ([PMID:36629374]).
The CCM2 variant spectrum comprises over 30 distinct alleles including nonsense, frameshift, splice-site, and structural variants, plus at least six missense changes within the phosphotyrosine-binding domain (e.g., c.365T>G (p.Leu122Arg)) that abolish CCM1 interaction ([PMID:31937560]).
Functional characterization shows that CCM2 binds CCM3 via an LD-like motif to stabilize both proteins against proteasomal degradation and supports endothelial network formation; pathogenic CCM2 missense and truncating mutants disrupt CCM1-CCM2 binding and complex assembly ([PMID:25825518], [PMID:25525273]). Cellular CCM2 knockdown leads to altered cytoskeletal protein expression and impaired tube formation, consistent with a loss-of-function mechanism ([PMID:24770493]).
No refuting studies on CCM2’s role in FCCM have been reported, and potential modifiers such as NOTCH3 and PTEN may influence disease severity through oxidative stress pathways ([PMID:35883785]).
Integration of genetic segregation, multiple unrelated probands, and coherent functional data meets criteria for a strong gene–disease association. Key take-home: Routine CCM2 genotyping enables definitive FCCM diagnosis, informs family counseling, and guides research into targeted interventions.
Gene–Disease AssociationStrongNine unrelated probands with heterozygous LoF and missense CCM2 variants segregating in multiple families, with concordant functional data Genetic EvidenceStrong9 probands with CCM2 variants (8 loss-of-function, 6 damaging missense) in autosomal dominant FCCM, with segregation in ~60 relatives Functional EvidenceModerateProtein interaction and cellular assays demonstrate loss-of-function via disrupted CCM1-CCM2 binding and impaired endothelial network formation |