This sequence change creates a premature translational stop signal (p.Arg388*) in the CYP7B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP7B1 are known to be pathogenic (PMID: 9802883, 19363635, 19439420, 21541746, 21567895, 28039895). This variant is present in population databases (rs72554620, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia and neonatal liver failure (PMID: 9802883, 18252231, 19812052). ClinVar contains an entry for this variant (Variation ID: 6100). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004820.5(CYP7B1):c.1162C>T (p.Arg388Ter)
Germline
Classification
Help
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.
(6)
Help
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
6
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.1162C>T (p.Arg388Ter)
Variation ID: 6100 Accession: VCV000006100.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8q12.3 8: 64604753 (GRCh38) [ NCBI UCSC ] 8: 65517310 (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 15, 2018 Oct 8, 2024 Sep 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004820.5:c.1162C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004811.1:p.Arg388Ter nonsense NM_001324112.2:c.1162C>T NP_001311041.1:p.Arg388Ter nonsense NC_000008.11:g.64604753G>A NC_000008.10:g.65517310G>A NG_008338.2:g.199039C>T - Protein change
- R388*
- Other names
- -
- Canonical SPDI
- NC_000008.11:64604752:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
521 | 574 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 20, 2023 | RCV000006474.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 1, 2008 | RCV000006473.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 11, 2023 | RCV000800899.9 |
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
(Sep 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Spastic paraplegia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000940642.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg388*) in the CYP7B1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg388*) in the CYP7B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP7B1 are known to be pathogenic (PMID: 9802883, 19363635, 19439420, 21541746, 21567895, 28039895). This variant is present in population databases (rs72554620, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia and neonatal liver failure (PMID: 9802883, 18252231, 19812052). ClinVar contains an entry for this variant (Variation ID: 6100). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 5A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329532.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The observed stop gained c.1162C>T(p.Arg388Ter) variant in CYP7B1 gene has been reported previously in homozygous state in multiple individuals affected with hereditary spastic paraplegia (Schüle … (more)
The observed stop gained c.1162C>T(p.Arg388Ter) variant in CYP7B1 gene has been reported previously in homozygous state in multiple individuals affected with hereditary spastic paraplegia (Schüle R, et al., 2010; Tsaousidou MK, et al., 2008; Siam A, et al., 2012). Functional studies demonstrate that this variant leads to protein truncation and is expected to produce a non-functional gene product (Siam A, et al., 2012). The c.1162C>T variant has been reported with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts a damaging effect on protein structure and function for this variant. The nucleotide change c.1162C>T in CYP7B1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg388Ter) in the CYP7B1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in CYP7B1 gene have been previously reported to be pathogenic (Goizet C, et al., 2009). For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the musculoskeletal system (present)
|
|
|
Pathogenic
(Feb 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 5A
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367373.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2.
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 5A
Affected status: yes
Allele origin:
unknown
|
Paris Brain Institute, Inserm - ICM
Accession: SCV001451298.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Feb 01, 2008)
|
no assertion criteria provided
Method: literature only
|
BILE ACID SYNTHESIS DEFECT, CONGENITAL, 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026656.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Congenital Bile Acid Synthesis Defect 3 In a 10-week-old boy with a metabolic defect in bile acid synthesis involving a deficiency in 7-alpha-hydroxylation (CBAS3; 613812), … (more)
Congenital Bile Acid Synthesis Defect 3 In a 10-week-old boy with a metabolic defect in bile acid synthesis involving a deficiency in 7-alpha-hydroxylation (CBAS3; 613812), Setchell et al. (1998) identified a homozygous C-to-T transition in the CYP7B1 gene, resulting in an arg388-to-ter (R388X) substitution. Spastic Paraplegia 5A In a patient with sporadic spastic paraplegia-5A (SPG5A; 270800), Tsaousidou et al. (2008) identified a homozygous 1162C-T transition in the CYP7B1 gene, resulting in an R388X substitution. The patient had symptoms of pure motor neuron degeneration without other features. Tsaousidou et al. (2008) postulated that the patient reported by Setchell et al. (1998) may have had loss of both alpha-hydroxylating enzymes, CYP7B1 and CYP7A1 (118455), to result in such a severe phenotype. (less)
|
|
|
Pathogenic
(Feb 01, 2008)
|
no assertion criteria provided
Method: literature only
|
SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026657.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Congenital Bile Acid Synthesis Defect 3 In a 10-week-old boy with a metabolic defect in bile acid synthesis involving a deficiency in 7-alpha-hydroxylation (CBAS3; 613812), … (more)
Congenital Bile Acid Synthesis Defect 3 In a 10-week-old boy with a metabolic defect in bile acid synthesis involving a deficiency in 7-alpha-hydroxylation (CBAS3; 613812), Setchell et al. (1998) identified a homozygous C-to-T transition in the CYP7B1 gene, resulting in an arg388-to-ter (R388X) substitution. Spastic Paraplegia 5A In a patient with sporadic spastic paraplegia-5A (SPG5A; 270800), Tsaousidou et al. (2008) identified a homozygous 1162C-T transition in the CYP7B1 gene, resulting in an R388X substitution. The patient had symptoms of pure motor neuron degeneration without other features. Tsaousidou et al. (2008) postulated that the patient reported by Setchell et al. (1998) may have had loss of both alpha-hydroxylating enzymes, CYP7B1 and CYP7A1 (118455), to result in such a severe phenotype. (less)
|
Comment:
Comment:
The observed stop gained c.1162C>T(p.Arg388Ter) variant in CYP7B1 gene has been reported previously in homozygous state in multiple individuals affected with hereditary spastic paraplegia (Schüle R, et al., 2010; Tsaousidou MK, et al., 2008; Siam A, et al., 2012). Functional studies demonstrate that this variant leads to protein truncation and is expected to produce a non-functional gene product (Siam A, et al., 2012). The c.1162C>T variant has been reported with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts a damaging effect on protein structure and function for this variant. The nucleotide change c.1162C>T in CYP7B1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg388Ter) in the CYP7B1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in CYP7B1 gene have been previously reported to be pathogenic (Goizet C, et al., 2009). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2.
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:
This sequence change creates a premature translational stop signal (p.Arg388*) in the CYP7B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP7B1 are known to be pathogenic (PMID: 9802883, 19363635, 19439420, 21541746, 21567895, 28039895). This variant is present in population databases (rs72554620, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia and neonatal liver failure (PMID: 9802883, 18252231, 19812052). ClinVar contains an entry for this variant (Variation ID: 6100). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed stop gained c.1162C>T(p.Arg388Ter) variant in CYP7B1 gene has been reported previously in homozygous state in multiple individuals affected with hereditary spastic paraplegia (Schüle R, et al., 2010; Tsaousidou MK, et al., 2008; Siam A, et al., 2012). Functional studies demonstrate that this variant leads to protein truncation and is expected to produce a non-functional gene product (Siam A, et al., 2012). The c.1162C>T variant has been reported with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts a damaging effect on protein structure and function for this variant. The nucleotide change c.1162C>T in CYP7B1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg388Ter) in the CYP7B1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in CYP7B1 gene have been previously reported to be pathogenic (Goizet C, et al., 2009). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic profiling of children with advanced cholestatic liver disease. | Shagrani M | Clinical genetics | 2017 | PMID: 28039895 |
| 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 |
| Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. | Schüle R | Journal of lipid research | 2010 | PMID: 19812052 |
| CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. | Goizet C | Brain : a journal of neurology | 2009 | PMID: 19439420 |
| Two novel CYP7B1 mutations in Italian families with SPG5: a clinical and genetic study. | Criscuolo C | Journal of neurology | 2009 | PMID: 19363635 |
| Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. | Tsaousidou MK | American journal of human genetics | 2008 | PMID: 18252231 |
| Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. | Setchell KD | The Journal of clinical investigation | 1998 | PMID: 9802883 |
Text-mined citations for rs72554620 ...
HelpThese 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 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.