ClinVar Miner

Submissions for variant NM_004820.5(CYP7B1):c.1456C>T (p.Arg486Cys) (rs116171274)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197085 SCV000253708 pathogenic Spastic paraplegia 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 486 of the CYP7B1 protein (p.Arg486Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs116171274, ExAC 0.1%). This variant has been reported in the literature in several individuals affected with hereditary spastic paraplegia. In these individuals, this variant was observed in either the homozygous state or compound heterozygous state (PMID: 19439420, 24117163, 21623769, 23812641). ClinVar contains an entry for this variant (Variation ID: 6107). A computational model and gene specific algorithm developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to affect ligand orientation and binding of the CYP7B1 protein, but this prediction has not been confirmed by published functional studies (PMID: 21541746). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000290486 SCV000330027 pathogenic not provided 2017-01-30 criteria provided, single submitter clinical testing The R486C variant in the CYP7B1 gene has been previously reported in the homozygous and compound heterozygous state in several individuals with spastic paraplegia (Goizet et al., 2009; Schlipf et al., 2011; Kumar et al., 2013; Roos et al., 2014). The NHLBI ESP Exome Sequencing Project reports R486C was observed in 10/8600 (0.12%) alleles from individuals of European background, although it was not noted in the homozygous state. The R486C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, R486C is considered a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000006481 SCV000474688 pathogenic Hereditary spastic paraplegia 5A 2018-05-18 criteria provided, single submitter clinical testing The CYP7B1 c.1456C>T (p.Arg486Cys) missense variant has been reported in at least six studies in individuals with an autosomal recessive form of spastic paraplegia, in which it was found in a homozygous state in three individuals and in a compound heterozygous state in nine individuals, including two siblings (Goizet et al. 2009; Schlipf et al. 2011; Noreau et al. 2012; Kumar et al. 2013; Roos et al. 2014; Kara et al. 2016). In at least seven of the compound heterozygotes the second variant was a frameshift or stop-gained variant. The p.Arg486Cys variant was absent from 494 control alleles and is reported at a frequency of 0.00298 in the European population of the 1000 Genomes Project. Based on the evidence, the p.Arg486Cys variant is classified as pathogenic for an autosomal recessive form of spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Unit for Genetic & Epidemiological Research on Neurological Disorders,Instituto de Investigação e Inovação em Saúde RCV000516130 SCV000574445 pathogenic Hereditary spastic paraplegia 2017-03-07 criteria provided, single submitter research
Athena Diagnostics Inc RCV000290486 SCV000613054 pathogenic not provided 2020-02-18 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000290486 SCV000708198 likely pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000290486 SCV001249591 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000290486 SCV001447079 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Paris Brain Institute,Inserm - ICM RCV000006481 SCV001451304 pathogenic Hereditary spastic paraplegia 5A criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000290486 SCV001713465 likely pathogenic not provided 2019-07-07 criteria provided, single submitter clinical testing PS4_moderate, PM2, PM3, PP5
Genomics England Pilot Project,Genomics England RCV000006481 SCV001760219 likely pathogenic Hereditary spastic paraplegia 5A criteria provided, single submitter clinical testing
OMIM RCV000006481 SCV000026664 pathogenic Hereditary spastic paraplegia 5A 2009-06-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000290486 SCV001741913 likely pathogenic not provided no assertion criteria provided clinical testing

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