The CYP27B1 c.1166G>A (p.Arg389His) missense variant has been reported in at least four studies in which it is found in a compound heterozygous state in five patients with vitamin D-dependent rickets (Wang et al. 1998; Wang et al. 2002; Yan et al. 2011; Durmaz et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in mouse testicular Leydig MA-10 cells revealed the variant resulted in no detectable 1-α-hydroxylase activity (Wang et al. 1998). Three other variants resulting in the abolition of enzyme activity are also found at the Arg389 residue (Sawada et al. 2001). Based on the evidence, the p.Arg389His variant is classified as likely pathogenic for vitamin D-dependent rickets. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000785.4(CYP27B1):c.1166G>A (p.Arg389His)
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/Likely 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
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NM_000785.4(CYP27B1):c.1166G>A (p.Arg389His)
Variation ID: 1669 Accession: VCV000001669.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q14.1 12: 57764147 (GRCh38) [ NCBI UCSC ] 12: 58157930 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 12, 2016 Oct 13, 2024 Sep 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000785.4:c.1166G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000776.1:p.Arg389His missense NC_000012.12:g.57764147C>T NC_000012.11:g.58157930C>T NG_007076.1:g.8047G>A O15528:p.Arg389His - Protein change
- R389H
- Other names
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CYP27B1, ARG389HIS (rs118204009)
- Canonical SPDI
- NC_000012.12:57764146:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00013
- 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. |
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| CYP27B1 | - | - |
GRCh38 GRCh37 |
451 | 465 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000001736.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2023 | RCV000481523.11 | |
| Pathogenic (2) |
criteria provided, single submitter
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Sep 18, 2024 | RCV001195099.4 |
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. |
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Likely pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Vitamin D-dependent rickets, type 1A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000380506.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The CYP27B1 c.1166G>A (p.Arg389His) missense variant has been reported in at least four studies in which it is found in a compound heterozygous state in … (more)
The CYP27B1 c.1166G>A (p.Arg389His) missense variant has been reported in at least four studies in which it is found in a compound heterozygous state in five patients with vitamin D-dependent rickets (Wang et al. 1998; Wang et al. 2002; Yan et al. 2011; Durmaz et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in mouse testicular Leydig MA-10 cells revealed the variant resulted in no detectable 1-α-hydroxylase activity (Wang et al. 1998). Three other variants resulting in the abolition of enzyme activity are also found at the Arg389 residue (Sawada et al. 2001). Based on the evidence, the p.Arg389His variant is classified as likely pathogenic for vitamin D-dependent rickets. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
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Pathogenic
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000564924.4
First in ClinVar: Apr 27, 2017 Last updated: Aug 13, 2023 |
Comment:
Functional studies demonstrate that the R389H variant has no detectable 1-alpha-hydroxylase activity (Wang et al., 1998); In silico analysis supports that this missense variant has … (more)
Functional studies demonstrate that the R389H variant has no detectable 1-alpha-hydroxylase activity (Wang et al., 1998); 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: 17488797, 22190362, 23483640, 22443290, 24308945, 9837822, 12050193, 18394115, 11737215, 21700898, 31589614) (less)
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Pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578500.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the CYP27B1 protein (p.Arg389His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the CYP27B1 protein (p.Arg389His). This variant is present in population databases (rs118204009, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive vitamin D-dependent rickets, type I (VDDR1A) (PMID: 9837822, 12050193, 17488797, 18394115, 22443290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1669). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27B1 protein function. Experimental studies have shown that this missense change affects CYP27B1 function (PMID: 9837822). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368391.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PM3_VSTR, PM5_STR, PS3_SUP, PM2_SUP, PP3, PP4; Identified as compund heterozygous with NM_000785.4:c.1427T>C
Clinical Features:
Hypophosphatemic rickets (present) , Genu valgum (present) , Hypotonia (present) , Decreased circulating vitamin D concentration (present)
Sex: female
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004027271.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Pathogenic
(Mar 01, 2013)
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no assertion criteria provided
Method: literature only
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VITAMIN D HYDROXYLATION-DEFICIENT RICKETS, TYPE 1A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021892.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 12, 2016 |
Comment on evidence:
In affected members of 2 unrelated families with vitamin D-dependent rickets type I (264700), Wang et al. (1998) identified compound heterozygosity for 2 mutations in … (more)
In affected members of 2 unrelated families with vitamin D-dependent rickets type I (264700), Wang et al. (1998) identified compound heterozygosity for 2 mutations in the CYP27B1 gene: an arg389-to-his (R389H) substitution and a 1-bp deletion (609506.0007). One family was from the United States and the other was French Canadian. In patients with VDDR I, Wang et al. (2002) found the R389H mutation in compound heterozygosity with a 5-bp deletion/6-bp insertion (609506.0013) and with a leu343-to-phe mutation (L343F; 609506.0016). The R389H mutation occurred in strand 4 of beta-sheet-1 of the P450c1-alpha protein (Wang et al., 1998) and results in a totally inactive protein (Wang et al., 2002). Possible Association with Multiple Sclerosis By whole-exome sequencing of 43 probands with multiple sclerosis (MS; 126200), each from a family in which 4 or more individuals had MS, Ramagopalan et al. (2011) found that 1 patient had a heterozygous R389H substitution (rs118204009) in the CYP27B1 gene that was found to be present in all 4 (100%) affected family members and 33% of genotyped unaffected family members. This variant was also found to be overtransmitted in an analysis of 3,046 parent-affected child trios (p = 1 x 10(-5)) and in a further 422 parent-affected sib pairs (p = 0.046). None of the individuals had evidence of VDDR1A. None of the individuals were of French Canadian origin. Serum from 1 individual with the R389H mutation showed low calcitriol levels compared to controls, suggesting that heterozygosity for loss-of-function alleles results in lower calcitriol levels. Overall, the findings supported a causative role for variation in the CYP27B1 gene in MS risk, which correlated with the geographic latitude gradient that appeared to influence disease risk. Ban et al. (2013) found no significant association between the R389H variant and MS among 495 multiplex families, 2,092 single affected families, and 4,594 patients with the disorder compared to 3,583 controls. None of the familial cases carried the variant. Five patients (0.07%) and 2 controls (0.6%) were heterozygous for the variant. Barizzone et al. (2013) also found no association between the R389H variant and MS among 2,608 patients and 1,987 controls from Italy and Belgium. Plasma measurement of 1 MS patient and 1 unaffected individual with a heterozygous R389H variant showed no decrease in 1,25-dihydroxyvitamin D levels. Ban et al. (2013) and Barizzone et al. (2013) independently concluded that mutant CYP27B1 alleles do not influence the risk of developing MS. (less)
|
Comment:
Comment:
Functional studies demonstrate that the R389H variant has no detectable 1-alpha-hydroxylase activity (Wang et al., 1998); 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: 17488797, 22190362, 23483640, 22443290, 24308945, 9837822, 12050193, 18394115, 11737215, 21700898, 31589614)
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the CYP27B1 protein (p.Arg389His). This variant is present in population databases (rs118204009, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive vitamin D-dependent rickets, type I (VDDR1A) (PMID: 9837822, 12050193, 17488797, 18394115, 22443290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1669). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27B1 protein function. Experimental studies have shown that this missense change affects CYP27B1 function (PMID: 9837822). For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PM3_VSTR, PM5_STR, PS3_SUP, PM2_SUP, PP3, PP4; Identified as compund heterozygous with NM_000785.4:c.1427T>C
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:
The CYP27B1 c.1166G>A (p.Arg389His) missense variant has been reported in at least four studies in which it is found in a compound heterozygous state in five patients with vitamin D-dependent rickets (Wang et al. 1998; Wang et al. 2002; Yan et al. 2011; Durmaz et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in mouse testicular Leydig MA-10 cells revealed the variant resulted in no detectable 1-α-hydroxylase activity (Wang et al. 1998). Three other variants resulting in the abolition of enzyme activity are also found at the Arg389 residue (Sawada et al. 2001). Based on the evidence, the p.Arg389His variant is classified as likely pathogenic for vitamin D-dependent rickets. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
Functional studies demonstrate that the R389H variant has no detectable 1-alpha-hydroxylase activity (Wang et al., 1998); 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: 17488797, 22190362, 23483640, 22443290, 24308945, 9837822, 12050193, 18394115, 11737215, 21700898, 31589614)
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the CYP27B1 protein (p.Arg389His). This variant is present in population databases (rs118204009, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive vitamin D-dependent rickets, type I (VDDR1A) (PMID: 9837822, 12050193, 17488797, 18394115, 22443290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1669). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27B1 protein function. Experimental studies have shown that this missense change affects CYP27B1 function (PMID: 9837822). For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PM3_VSTR, PM5_STR, PS3_SUP, PM2_SUP, PP3, PP4; Identified as compund heterozygous with NM_000785.4:c.1427T>C
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| No evidence for a role of rare CYP27B1 functional variations in multiple sclerosis. | Barizzone N | Annals of neurology | 2013 | PMID: 23483640 |
| No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. | Ban M | Annals of neurology | 2013 | PMID: 23444327 |
| Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. | Durmaz E | Clinical endocrinology | 2012 | PMID: 22443290 |
| Rare variants in the CYP27B1 gene are associated with multiple sclerosis. | Ramagopalan SV | Annals of neurology | 2011 | PMID: 22190362 |
| Vitamin D-dependent rickets type 1: a rare, but treatable, cause of severe hypotonia in infancy. | Yan Y | Journal of child neurology | 2011 | PMID: 21700898 |
| Co-occurrence of vitamin D-dependent rickets type 1 and phenylketonuria. | Søvik O | Acta paediatrica (Oslo, Norway : 1992) | 2008 | PMID: 18394115 |
| Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. | Kim CJ | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17488797 |
| Novel gene mutations in patients with 1alpha-hydroxylase deficiency that confer partial enzyme activity in vitro. | Wang X | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12050193 |
| Structure-function analysis of CYP27B1 and CYP27A1. Studies on mutants from patients with vitamin D-dependent rickets type I (VDDR-I) and cerebrotendinous xanthomatosis (CTX). | Sawada N | European journal of biochemistry | 2001 | PMID: 11737215 |
| Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. | Wang JT | American journal of human genetics | 1998 | PMID: 9837822 |
Text-mined citations for rs118204009 ...
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 20, 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.