rs116171274

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBS2_Supporting

The NM_004820.5(CYP7B1):c.1456C>T(p.Arg486Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000777 in 1,613,374 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 4 hom. )

Consequence

CYP7B1
NM_004820.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: 5.74

Publications

20 publications found

Variant links:

Genes affected

CYP7B1 (HGNC:2652): (cytochrome P450 family 7 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway of extrahepatic tissues, which converts cholesterol to bile acids. This enzyme likely plays a minor role in total bile acid synthesis, but may also be involved in the development of atherosclerosis, neurosteroid metabolism and sex hormone synthesis. Mutations in this gene have been associated with hereditary spastic paraplegia (SPG5 or HSP), an autosomal recessive disorder. [provided by RefSeq, Apr 2016]

CYP7B1 Gene-Disease associations (from GenCC):

congenital bile acid synthesis defect 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
hereditary spastic paraplegia 5A
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

CYP7B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

PP5

Variant 8-64596707-G-A is Pathogenic according to our data. Variant chr8-64596707-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CYP7B1	NM_004820.5 link	c.1456C>T	p.Arg486Cys	missense_variant	Exon 6 of 6	ENST00000310193.4	NP_004811.1
CYP7B1	XM_017014002.2 link	c.1522C>T	p.Arg508Cys	missense_variant	Exon 7 of 7		XP_016869491.1
CYP7B1	NM_001324112.2 link	c.1234-6863C>T		intron_variant	Intron 5 of 6		NP_001311041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP7B1	ENST00000310193.4 link	c.1456C>T	p.Arg486Cys	missense_variant	Exon 6 of 6	1	NM_004820.5	ENSP00000310721.3
CYP7B1	ENST00000523954.1 link	n.508-6863C>T		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000523

AC:

131

AN:

250608

AF XY:

0.000509

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000988

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000797

AC:

1164

AN:

1461226

Hom.:

Cov.:

AF XY:

0.000733

AC XY:

533

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33412

American (AMR)

AF:

0.0000672

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86126

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000971

AC:

1080

AN:

1111740

Other (OTH)

AF:

0.000696

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000592

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41512

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000750

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Mar 18, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 20, 2018

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP4, PM2_moderate, PM3, PS4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 16, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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, 37273706, 34983064, 24927729, 27077743, 34758253, 21623769, 37152446, 24117163, 21541746, 23812641, 28832565, 22384504, 27217339, 27957547, 27879216, 32202070, 31980526, 33160247, 31847883, 35944583, 37024986, 38361118, 38499745, 19439420)

Feb 17, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP7B1: PM3:Very Strong, PM2:Supporting, PP1, PP4

Hereditary spastic paraplegia 5A

Pathogenic:8

Jun 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 18, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 1246 heterozygote(s), 4 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic and likely pathogenic by multiple clinical laboratories (ClinVar); Missense variant consistently predicted to be damaging by an in silico tool or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to cysteine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4; highest allele count: 84 heterozygote(s), 0 homozygote(s)) - Variant is located in the annotated p450 domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with congenital bile acid synthesis defect, 3 (MIM#3613812) and autosomal recessive spastic paraplegia 5A (MIM#270800); Inheritance information for this variant is not currently available in this individual.

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 03, 2021

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Feb 23, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

Feb 04, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Pathogenic:3

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Jun 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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.

CYP7B1-related disorder

Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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 et al. 2013. PubMed ID: 23812641). This variant is reported in 0.098% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is reported as pathogenic or likely pathogenic in ClinVar by many outside laboratories. This variant is interpreted as pathogenic.

Spastic paraplegia

Pathogenic:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYP7B1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Hereditary spastic paraplegia 5A;C3151147:Congenital bile acid synthesis defect 3

Pathogenic:1

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.1

PhyloP100

5.7

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.76

ClinPred

0.42

GERP RS

5.5

Varity_R

0.63

gMVP

0.94

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over