CWF19L1 was first reported in relation to autosomal recessive spinocerebellar ataxia in 2014 (Burns R, et al., PMID: 25361784). The CWF19L1 gene is thought to play a role in cell cycle control, endosomal trafficking and mRNA processing (PMID: 36357319). Autosomal recessive cerebellar ataxia due to variants in CWF19L1 is characterized by gait, limb, and truncal ataxia, developmental delay, hypotonia, intellectual disability, and cerebellar atrophy or hypoplasia on brain imaging. Other features may be present as well and patients typically, but not always, have an early age of onset (PMID: 36453471).
Fourteen variants (4 canonical splice-site, 5 missense, 2 frameshift, 2 nonsense, 1 in-frame deletion) that have been reported in 12 probands in 9 publications (PMIDs: 25361784, 26197978, 27016154, 38681507, 36357319, 36530930, 36453471, 37752213, 33012273) 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 is loss of function.
This gene-disease relationship is also supported by a morpholino-mediated knockdown of CWF19L1 in zebrafish that led to cerebellar and movement abnormalities (PMID: 25361784).
In summary, there is definitive evidence supporting the relationship between CWF19L1 and autosomal recessive spinocerebellar ataxia. 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 Ataxia GCEP on the meeting date May 14, 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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