Submissions for variant NM_004820.5(CYP7B1):c.850+5G>C

gnomAD frequency: 0.00010  dbSNP: rs202155727

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523484	SCV000621637	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CYP7B1 gene. The c.850+5 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.850+5 G>C variant is observed in 33/125006 (0.03%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). This substitution occurs at a position that is conserved in mammals. However, several in-silico splice prediction models predict that c.850+5 G>C does not impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818995	SCV000959634	uncertain significance	Spastic paraplegia	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the CYP7B1 gene. It does not directly change the encoded amino acid sequence of the CYP7B1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs202155727, gnomAD 0.03%). 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: 452800). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848918	SCV002104565	uncertain significance	Hereditary spastic paraplegia	2019-08-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905317	SCV004725263	likely benign	CYP7B1-related disorder	2022-01-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).