NPRL3 was first reported in relation to autosomal dominant focal epilepsy (a form of epilepsy characterized by seizures that are localized to one area or side of the brain) in 2016 (Ricos et al., PMID: 26505888). Six frameshift and two stop loss variants reported in eight probands across six publications are included in this curation (PMIDs: 26505888, 26285051, 27173016, 34868250, 35136953, and 26786403). More evidence, such as segregation data, is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, reduced penetrance has been demonstrated in multiple families, and seizure foci may vary across family members (PMIDs: 35136953, 34868250). The primary mechanism of disease is thought to be LOF (PMID: 34868250).
In summary, there is definitive evidence to support the relationship between NPRL3 and autosomal dominant focal epilepsy (MONDO:0005384). 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 Epilepsy Gene Curation Expert Panel on October 18, 2022 (SOP Version 9).
As of August 1, 2023, this record underwent administrative changes to update scoring for two missense variants: p.Glu249Lys and p.Arg92Gln (PMID:26505888). Functional studies demonstrate that these variants can rescue mTOR activity in CRISPR/CAS knockout cells, bringing the pathogenicity of these two variants into question (PMID:31639411). Therefore, they are now both scored at zero points. No other new evidence has been reviewed or added, and the final classification of definitive did not change.
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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