Submissions for variant NM_004820.5(CYP7B1):c.1354C>T (p.Arg452Ter)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578856	SCV000681166	likely pathogenic	not provided	2017-12-04	criteria provided, single submitter	clinical testing	The R452X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R452X variant is a nonsense variant in the C-terminus predicted to result in protein truncation, as the last 55 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014). The R452X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Paris Brain Institute, Inserm - ICM	RCV001391411	SCV001451303	pathogenic	Hereditary spastic paraplegia 5A		criteria provided, single submitter	clinical testing
Invitae	RCV003767256	SCV004685475	pathogenic	Spastic paraplegia	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg452*) in the CYP7B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the CYP7B1 protein. This variant is present in population databases (rs769676029, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CYP7B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 489179). This variant disrupts a region of the CYP7B1 protein in which other variant(s) (p.Arg486Cys) have been determined to be pathogenic (PMID: 19439420, 21623769, 23812641, 24117163). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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