ClinVar Miner

Submissions for variant NM_004820.5(CYP7B1):c.1088C>T (p.Ser363Phe)

gnomAD frequency: 0.00001  dbSNP: rs121908610
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001847590 SCV002104542 uncertain significance Hereditary spastic paraplegia 2021-10-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001847590 SCV002598804 likely pathogenic Hereditary spastic paraplegia 2022-09-27 criteria provided, single submitter clinical testing Variant summary: CYP7B1 c.1088C>T (p.Ser363Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251244 control chromosomes. c.1088C>T has been reported in the literature in multiple individuals from one consanguineous family affected with features of Hereditary Spastic Paraplegia, Type 5a that was identified by linkage analysis (example, Tsaousidou_2008, cited by Chou_2020, Schols_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV003750776 SCV004523879 pathogenic Spastic paraplegia 2023-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 363 of the CYP7B1 protein (p.Ser363Phe). This variant is present in population databases (rs121908610, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18252231). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP7B1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006475 SCV000026658 pathogenic Hereditary spastic paraplegia 5A 2008-02-01 no assertion criteria provided literature only

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