VCV000006103.19 - ClinVar

NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)

Variation ID: 6103 Accession: VCV000006103.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q12.3 8: 64596913 (GRCh38) [ NCBI UCSC ] 8: 65509470 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 8, 2024	Dec 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004820.5:c.1250G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004811.1:p.Arg417His	missense
NM_001324112.2:c.1234-7069G>A		intron variant
NC_000008.11:g.64596913C>T
NC_000008.10:g.65509470C>T
NG_008338.2:g.206879G>A
	O75881:p.Arg417His

... more HGVS ... less HGVS

Protein change

R417H

Other names

Canonical SPDI

NC_000008.11:64596912:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD) 0.00006

Links

ClinGen: CA210942 UniProtKB: O75881#VAR_044385 OMIM: 603711.0004 dbSNP: rs121908611 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CYP7B1		-	-	GRCh38 GRCh37	520	573

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary spastic paraplegia 5A	Likely pathogenic (2)	criteria provided, single submitter	Oct 4, 2018	RCV000006477.7
Spastic paraplegia	Pathogenic (1)	criteria provided, single submitter	Dec 2, 2023	RCV000206595.10
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 15, 2023	RCV000329074.3
Hereditary spastic paraplegia	Pathogenic (1)	criteria provided, single submitter	Oct 15, 2020	RCV001847591.3
CYP7B1-related disorder	Pathogenic (1)	no assertion criteria provided	Feb 27, 2024	RCV003894794.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 20, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330028.5 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: 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 … (more) 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. (less)
Likely pathogenic (Oct 04, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary spastic paraplegia 5A (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967608.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (6) PubMed: 19439420‚ 18252231‚ 21541746‚ 24658845‚ 21567895‚ 22384504 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Oct 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002104547.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Pathogenic (Mar 15, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV004229199.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (12) PubMed: 22384504‚ 21541746‚ 31589614‚ 34426522‚ 33160247‚ 25324891‚ 29228183‚ 29126212‚ 17503452‚ 18252231‚ 19439420‚ 7987300 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Spastic paraplegia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261512.8 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 18252231‚ 19439420‚ 22384504‚ 21567895‚ 24658845 Comment: 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). … (more) 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. (less)
Pathogenic (Jun 01, 2009)	no assertion criteria provided Method: literature only	SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026660.2 First in ClinVar: Apr 04, 2013 Last updated: Feb 18, 2017	Publications: PubMed (3) PubMed: 7987300‚ 18252231‚ 19439420 Comment on evidence: In affected members of 2 consanguineous Tunisian families with spastic paraplegia-5A (SPG5A; 270800) reported by Hentati et al. (1994), Tsaousidou et al. (2008) identified a … (more) In affected members of 2 consanguineous Tunisian families with spastic paraplegia-5A (SPG5A; 270800) reported by Hentati et al. (1994), Tsaousidou et al. (2008) identified a homozygous 1250G-A transition in exon 6 of the CYP7B1 gene, resulting in an arg417-to-his (R417H) substitution. Goizet et al. (2009) identified a homozygous R417H mutation in affected members of a family with SPG5A and in a patient with sporadic disease. Another family was compound heterozygous for R417H and F470I (603711.0008). Patients who were homozygous for the mutation presented a pure SPG, with mild to moderate lower limb involvement and decreased vibratory sensation. Some patients showed mild upper limb weakness. (less)
Pathogenic (Feb 27, 2024)	no assertion criteria provided Method: clinical testing	CYP7B1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004714941.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Elevated hydroxycholesterols in Norwegian patients with hereditary spastic paraplegia SPG5.	Prestsæter S	Journal of the neurological sciences	2020	PMID: 33160247
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5.	Marelli C	Brain : a journal of neurology	2018	PMID: 29228183
Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.	Schöls L	Brain : a journal of neurology	2017	PMID: 29126212
Somatosensory conduction pathway in spastic paraplegia type 5.	Vanotti A	Journal of clinical neurology (Seoul, Korea)	2014	PMID: 25324891
Liver disease in infancy caused by oxysterol 7 α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid.	Dai D	Journal of inherited metabolic disease	2014	PMID: 24658845
CYP7B1 mutations in French-Canadian hereditary spastic paraplegia subjects.	Noreau A	The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques	2012	PMID: 22384504
Comparative modeling of 25-hydroxycholesterol-7α-hydroxylase (CYP7B1): ligand binding and analysis of hereditary spastic paraplegia type 5 CYP7B1 mutations.	Siam A	Journal of molecular modeling	2012	PMID: 21541746
Successful heterozygous living donor liver transplantation for an oxysterol 7α-hydroxylase deficiency in a Japanese patient.	Mizuochi T	Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society	2011	PMID: 21567895
CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.	Goizet C	Brain : a journal of neurology	2009	PMID: 19439420
Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.	Tsaousidou MK	American journal of human genetics	2008	PMID: 18252231
Spastic paraplegia 5: Locus refinement, candidate gene analysis and clinical description.	Klebe S	American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics	2007	PMID: 17503452
Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity.	Hentati A	Human molecular genetics	1994	PMID: 7987300
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Text-mined citations for rs121908611 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908611 ...