8-64596707-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 5.74

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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 [Likely_pathogenic]. Clinvar id is 6107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-64596707-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP7B1	NM_004820.5	c.1456C>T	p.Arg486Cys	missense_variant	6/6	ENST00000310193.4
CYP7B1	XM_017014002.2	c.1522C>T	p.Arg508Cys	missense_variant	7/7
CYP7B1	NM_001324112.2	c.1234-6863C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP7B1	ENST00000310193.4	c.1456C>T	p.Arg486Cys	missense_variant	6/6	1	NM_004820.5	P1
CYP7B1	ENST00000523954.1	n.508-6863C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152030 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000523 AC: 131 AN: 250608 Hom.: 0 AF XY: 0.000509 AC XY: 69 AN XY: 135528

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 SAS exome AF: 0.0000328

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.: 4 Cov.: 31 AF XY: 0.000733 AC XY: 533 AN XY: 726904

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000971

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000565 AC XY: 42 AN XY: 74392

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000859 Hom.: 0

Bravo AF: 0.000555

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 18, 2022	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 03, 2023	PP1, PP4, PM2, PM3, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CYP7B1: PM3:Very Strong, PM2:Supporting, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2022	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hereditary spastic paraplegia 5A Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 18, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Sep 03, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 04, 2022	- -

Hereditary spastic paraplegia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2023	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. -
Pathogenic, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Dec 12, 2016	- -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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. -

CYP7B1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2023

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. -

Hereditary spastic paraplegia 5A;C3151147:Congenital bile acid synthesis defect 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.91
MPC		0.51
ClinPred		0.42	T
GERP RS		5.5
Varity_R		0.63
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs116171274; hg19: chr8-65509264;