rs121908611

Positions:

• chr8-64596913-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004820.5(CYP7B1):​c.1250G>A​(p.Arg417His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,611,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R417C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: CYP7B1 NM_004820.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-64596914-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 586668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 8-64596913-C-T is Pathogenic according to our data. Variant chr8-64596913-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP7B1	NM_004820.5	c.1250G>A	p.Arg417His	missense_variant	6/6	ENST00000310193.4
CYP7B1	XM_017014002.2	c.1316G>A	p.Arg439His	missense_variant	7/7
CYP7B1	NM_001324112.2	c.1234-7069G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP7B1	ENST00000310193.4	c.1250G>A	p.Arg417His	missense_variant	6/6	1	NM_004820.5	P1
CYP7B1	ENST00000523954.1	n.508-7069G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 250000 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000418 AC: 61 AN: 1459026 Hom.: 0 Cov.: 30 AF XY: 0.0000372 AC XY: 27 AN XY: 725958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000469

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74320

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2017	The R417H variant in the CYP7B1 gene has been reported previously multiple times in the homozygous and compound heterozygous state in individuals with spastic paraplegia (Tsaousidou et al., 2008; Goizet et al., 2009; Marelli et al., 2017). Additional studies have also indicated that pathogenic variants involving R417 may impair catalytic function and indirectly affect ligand binding (Siam et al., 2012). The R417H variant is observed in 2/18838 (0.003%) alleles from individuals of Asian background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). It is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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. Additionally, other missense variants at the same position (R417C and R417G) have been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014). We interpret R417H as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with spastic paraplegia in multiple families. 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. Computational tools predict that this variant is damaging. -

Hereditary spastic paraplegia 5A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 04, 2018	The p.Arg417His variant in CYP7B1 has been reported in 6 individuals with spasti c paraplegia and two young children with oxysterol 7a-hydroxylase deficiency, an d segregated with spastic paraplegia in 10 affected relatives from 4 families (T saousidou 2008, Goizet 2009, Mizuochi 2011, Noreau 2012, Dai 2014). This variant has been identified in 2/18838 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 6103). Molecular modeling studies, computational prediction tool s, and conservation analysis suggest that the p.Arg417His variant may impact the protein, though this information is not predictive enough to determine pathogen icity (Siam 2012). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classifi ed as likely pathogenic for autosomal recessive spastic paraplegia type 5. ACMG/ AMP criteria applied: PM3_Strong, PM2, PP1_Moderate, PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -

CYP7B1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The CYP7B1 c.1250G>A variant is predicted to result in the amino acid substitution p.Arg417His. This variant was reported in the homozygous state in an individual with hereditary spastic paraplegia (Family 2, Tsaousidou et al 2008. PubMed ID: 18252231). This variant was also identified in the heterozygous state, and interpreted as pathogenic, in three individuals in a study utiziling exome sequencing for preconception carrier screening (Supplementary Table 1, Capalbo A et al 2019. PubMed ID: 31589614). Comparative modeling of CYP7B1 shows that the R417 amino acid resides in the meander region, which is the conserved PERF region, and suggests that any variant involving the R417 amino acid would be predicted to severely affect enzyme function (Siam A et al 2011. PubMed ID: 21541746). In addition, other variants impact the R417 amino acids have also been reported in individuals with hereditary spastic paraplegia (Goizet et al. 2009. PubMed ID: 19439420; Cao et al. 2011. PubMed ID: 21452256). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. Taken together, we interpret this variant as pathogenic. -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 417 of the CYP7B1 protein (p.Arg417His). This variant is present in population databases (rs121908611, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 18252231, 19439420, 22384504). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6103). 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 expected to disrupt CYP7B1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg417 amino acid residue in CYP7B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19439420, 21567895, 24658845). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		1.0
MPC		0.49
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908611; hg19: chr8-65509470;