ZFYVE27 was first reported in relation to autosomal dominant hereditary spastic paraplegia (HSP) in 2006 (Mannan et al., PMID: 16826525). In this study, a missense variant (c.572G>T; p.G191V) was identified in three related individuals with HSP, following targeted sequencing of the ZFYVE27 gene. No whole exome or genome approaches were used, and the authors did not state whether any other HSP genes had been previously tested. The population allele frequencies for the p.G191V variant identified in this family are higher than would be expected for disease-causing variants, and therefore was not scored. A second family was reported in 2015 (PMID: 25497598) with a splice acceptor variant [c.8052-2A-G]. This variant was also reported in the general population and was not scored. The assertion that the variant in ZFYVE27 was causative was attributed to the original Mannan et al., study. Experimental cell models have demonstrated that ZFYVE27 was found to localize predominantly to the tubular endoplasmic reticulum (ER) and forced expression of protrudin promoted the formation and stabilization of the tubular ER network (PMID: 24668814). However, there was conflicting evidence whether the G191V variant impaired the function of ZFYVE27 protein (PMIDs: 18606302 and 24668814).
In summary, the evidence supporting the relationship between ZFYVE27 and autosomal dominant hereditary spastic paraplegia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role ZFYVE27 plays in this disease. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on February 2, 2023 (SOP Version 9).
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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