CFAP410, previously C21orf2, was first reported in relation to amyotrophic lateral sclerosis (ALS) in 2016 (van Rheenen et al., PMID: 27455348). CFAP410 encodes cilia-and flagella-associated protein 410 and has a role in ciliogenesis and DNA damage repair. CFAP410 has also been associated with autosomal recessive retinal dystrophy with macular staphyloma and autosomal recessive axial spondylometaphyseal dysplasia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern and phenotypic variability among these diseases. Therefore, the following disease entities have been split into separate disease entities: semi-dominant ALS (OMIM: 105400), autosomal recessive retinal dystrophy with macular staphyloma (OMIM: 617547) and autosomal recessive axial spondylometaphyseal dysplasia (OMIM: 602271). The association between CFAP410 and ALS was first established in a genome-wide variant case-control analysis that identified an association between a risk variant in the gene, described as rs75087725 (Val58Leu), and the phenotype based on the genome sequencing of 12,577 ALS cases and 23,475 controls (van Rheenen et al., PMID:27455348). Per criteria set by the ALS GCEP, the missense variant found in this study is outside the established gnomAD minor allele frequency cutoffs (<0.00005) and, while is unlikely to be a main cause of disease, reached a level of significance. To date, no causal variants in CFAP410 have been documented in ALS patients in the literature. The mechanism of pathogenicity is currently unclear. This gene-disease association is supported by experimental evidence describing expression of* CFAP410* in neuronal tissues, physical interaction with known ALS associated gene NEK1 and functional alterations in non-patient cells (PMIDs: 36131690, 26290490, and 32891887). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. It is important to understand that in the clinical diagnostic setting the identification of variants of uncertain significance may be common and variant interpretation must be completed with caution. This classification was approved by the ClinGen ALS GCEP on December 12, 2023.
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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