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

gnomAD frequency: 0.00051  dbSNP: rs116171274

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197085	SCV000253708	pathogenic	Spastic paraplegia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 486 of the CYP7B1 protein (p.Arg486Cys). This variant is present in population databases (rs116171274, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with hereditary spastic paraplegia. In these individuals, this variant was observed in either the homozygous state or compound heterozygous state (PMID: 19439420, 21623769, 23812641, 24117163). ClinVar contains an entry for this variant (Variation ID: 6107). An algorithm developed specifically for the CYP7B1 gene suggests that this missense change is likely to be deleterious (PMID: 21541746). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000290486	SCV000330027	pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 25073475, 24927729, 27077743, 21623769, 24117163, 21541746, 23812641, 28832565, 22384504, 27217339, 27957547, 27879216, 32202070, 31980526, 19439420)
Illumina Laboratory Services, 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	RCV000290486	SCV000613054	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with spastic paraplegia, this variant has been seen with a single recessive pathogenic variant in the same gene. Computational tools predict that this variant is damaging.
Eurofins Ntd Llc (ga)	RCV000290486	SCV000708198	likely pathogenic	not provided	2018-04-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000290486	SCV001249591	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	CYP7B1: PM3:Very Strong, PM2:Supporting, PP1, PP4
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	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	PP1, PP4, PM2, PM3, PS4
Genomics England Pilot Project, Genomics England	RCV000006481	SCV001760219	likely pathogenic	Hereditary spastic paraplegia 5A		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000516130	SCV002104551	pathogenic	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000006481	SCV002498645	pathogenic	Hereditary spastic paraplegia 5A	2021-09-03	criteria provided, single submitter	clinical testing	This sequence change in CYP7B1 is predicted to replace arginine with cysteine at codon 486 (p.(Arg486Cys)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the cytochrome P450 domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v2.1 is 0.1% (126/128,798 alleles, 0 homozygotes) in European (non-Finnish) population. The variant has been reported to segregate with spastic paraplegia in two affected family members from one family (PMID: 22384504 ). This variant has been detected in at least 16 individuals with pure or complicated hereditary spastic paraplegia (HSP). Of those individuals, five individuals were homozygous and eight were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 1943942, 21623769, 22384504, 23812641, 24117163, 27217339, 29228183). At least one patient with this variant displayed increased plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) ratio to total cholesterol, which is highly specific for CYP7B1-related HSP (PMID: 29228183). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1, PP3, PP4.
MGZ Medical Genetics Center	RCV000006481	SCV002580725	likely pathogenic	Hereditary spastic paraplegia 5A	2022-02-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476935	SCV002789040	pathogenic	Hereditary spastic paraplegia 5A; Congenital bile acid synthesis defect 3	2021-08-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000290486	SCV003830324	likely pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing
3billion	RCV000006481	SCV003841533	likely pathogenic	Hereditary spastic paraplegia 5A	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.052%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006107). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000516130	SCV004020995	pathogenic	Hereditary spastic paraplegia	2023-06-23	criteria provided, single submitter	clinical testing	Variant summary: CYP7B1 c.1456C>T (p.Arg486Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 250608 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYP7B1 causing Hereditary Spastic Paraplegia, Type 5a (0.00052 vs 0.0011), allowing no conclusion about variant significance. c.1456C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Hereditary Spastic Paraplegia, Type 5a (e.g. Goizet_2009, Schlipf_2011, Kumar_2013, Roos_2014). 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. The following publications have been ascertained in the context of this evaluation (PMID: 19439420, 23812641, 24117163, 21623769). Fifteen ClinVar submitters have assessed the variant since 2014: five classified the variant as likely pathogenic and ten as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398453	SCV004103442	pathogenic	CYP7B1-related disorder	2023-08-05	criteria provided, single submitter	clinical testing	The CYP7B1 c.1456C>T variant is predicted to result in the amino acid substitution p.Arg486Cys. This variant has been reported in either the homozygous state or compound heterozygous state in many patients with spastic paraplegia (Goizet et al. 2009. PubMed ID: 19439420; Schlipf et al. 2011. PubMed ID: 21623769; Roos et al. 2014. PubMed ID: 24117163; Kumar KR et al 2013. PubMed ID: 23812641). This variant is reported in 0.098% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-65509264-G-A) and is reported as pathogenic or likely pathogenic in ClinVar by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6107/). This variant is interpreted as pathogenic.
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000290486	SCV001957403	likely pathogenic	not provided		no assertion criteria provided	clinical testing