Submission Details

The USP7 gene is located on chromosome 16 at 16p13.2 and encodes the ubiquitin-specific protease 7, a deubiquitinating enzyme that is a component of the MAGEL2-USP7-TRIM27 (MUST) complex regulating WASH activity, endosomal actin assembly and protein recycling. USP7 also regulates MDM2-p53 pathway implicated in apoptosis and cell cycle. USP7 was first reported in relation to autosomal dominant USP7-related neurodevelopmental disorder in 2015 (26365382: Hao et al. 2015). At least eight unique de novo variants have been reported, including missense, frameshift, and stop-gained variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in two publications (26365382: Hao et al. 2015; 30679821: Fountain et al. 2019). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by protein interaction of USP with MAGE-L2 and TRIM27 to form a ligase complex that regulates WASH-mediated endosomal protein recycling (23452853: Hao et al. 2013) and a cell line with reduced USP7 showed impaired endosomal recycling (26365382: Hao et al. 2015). In summary, there is strong evidence to support the relationship between USP7 and autosomal dominant USP7-related neurodevelopmental disorder. An additional report in humans published three years from the first proposal of the association is needed to reach a definitive classification.

PubMed IDs:

26365382 30679821 23452853

Assertion Criteria:

Click here to view assertion criteria

https://www.clinicalgenome.org/site/assets/files/3975/gene-disease_validity_standard_operating_procedures_version_7-1.pdf

Submitter Submitted Date:

10/15/2020

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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