ClinVar Genomic variation as it relates to human health
NM_000785.4(CYP27B1):c.1319_1325dup (p.Phe443fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000785.4(CYP27B1):c.1319_1325dup (p.Phe443fs)
Variation ID: 279798 Accession: VCV000279798.27
- Type and length
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Microsatellite, 7 bp
- Location
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Cytogenetic: 12q14.1 12: 57763698-57763699 (GRCh38) [ NCBI UCSC ] 12: 58157481-58157482 (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 Oct 9, 2016 Jul 7, 2024 Mar 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000785.4:c.1319_1325dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000776.1:p.Phe443fs frameshift NM_000785.4:c.1319_1325dupCCCACCC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000785.4:c.1325_1326insCCCACCC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000785.3:c.1319_1325dup NC_000012.12:g.57763699GGGTGGG[3] NC_000012.11:g.58157482GGGTGGG[3] NG_007076.1:g.8482CCCACCC[3] - Protein change
- F443fs
- Other names
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- Canonical SPDI
- NC_000012.12:57763698:GGGTGGGGGGTGGG:GGGTGGGGGGTGGGGGGTGGG
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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 |
442 | 456 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000271425.13 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 5, 2020 | RCV001028038.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2021 | RCV001267045.4 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Mar 28, 2024 | RCV001808725.10 |
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
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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
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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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Pathogenic
(Jan 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000859294.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329329.5
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 66 amino acids are replaced with 23 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 66 amino acids are replaced with 23 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9837822, 22443290, 28587998, 22588163, 31980526, 25296067, 31589614, 33386952, 33004071, 25284246, 30282619, 33329754) (less)
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001223674.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe443Profs*24) in the CYP27B1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Phe443Profs*24) in the CYP27B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the CYP27B1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with vitamin D-dependent rickets (PMID: 9837822, 22443290, 25296067). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1325-1326insCCCACCC and 7bpdup. ClinVar contains an entry for this variant (Variation ID: 279798). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058545.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated … (more)
Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant was co-segregated with Vitamin D-dependent rickets, type I in multiple affected family members (PMID: 22443290, PP1_P). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279798, PMID:9837822). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000209, PM2_M). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 22443290,PM3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypophosphatemia (present) , Abnormality of the skeletal system (present)
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Pathogenic
(Jan 13, 2022)
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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:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002059960.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Age: 0-9 years
Sex: female
Ethnicity/Population group: Asian Indian
Geographic origin: India
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: no
Allele origin:
germline
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Payam Genetics Center, General Welfare Department of North Khorasan Province
Accession: SCV003914806.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023
Comment:
This variant is as a framshift that predicted to result in a loss or disruption of normal protein function through protein truncation. This variant is … (more)
This variant is as a framshift that predicted to result in a loss or disruption of normal protein function through protein truncation. This variant is not present in population databases (ExAC no frequency) and 1000 genomes. This variant has not been reported in the literature in individuals affected with CYP27B1-related conditions and Iranom ( Iranian population genom). This variant disrupts a region of the CYP27B1 protein (p.P445fs) in whichThis suggests that this is a clinically significant , and that disrupt it is likely to be disease-causing. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
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Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Ethnicity/Population group: Iranian
Geographic origin: Iran
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Pathogenic
(Nov 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004013971.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PVS1, PM2, PP5
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Pathogenic
(Jul 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041154.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jun 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004234250.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445226.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.1319_1325dupCCCACCC (p.F443Pfs*24) alteration, located in coding exon 8 of the CYP27B1 gene, consists of a duplication of 7 nucleotides at position 1319, causing a … (more)
The c.1319_1325dupCCCACCC (p.F443Pfs*24) alteration, located in coding exon 8 of the CYP27B1 gene, consists of a duplication of 7 nucleotides at position 1319, causing a translational frameshift with a predicted alternate stop codon after 24 amino acids. This alteration occurs at the 3' terminus of the CYP27B1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.8% (65/508 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). The p.F443Pfs*24 alteration has been reported in both a homozygous and compound heterozygous state with other alterations in the CYP27B1 gene in several unrelated patients with vitamin D-dependent rickets (Wang, 1998; Durmaz, 2012; Ito, 2014; Dursun, 2019; Li, 2020). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005040384.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: CYP27B1 c.1319_1325dupCCCACCC (p.Phe443ProfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. … (more)
Variant summary: CYP27B1 c.1319_1325dupCCCACCC (p.Phe443ProfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 0.00022 in 251182 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYP27B1 causing Vitamin D-dependent rickets (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.1319_1325dupCCCACCC has been reported in the literature in multiple individuals affected with Vitamin D-dependent rickets (example: Kaygusuz_2021). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33386952). ClinVar contains an entry for this variant (Variation ID: 279798). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 01, 1998)
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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
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OMIM
Accession: SCV000021888.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016 |
Comment on evidence:
The gene for 1-alpha hydroxylase contains a duplicated sequence 5-prime-CCCACCC CCCACCC-3-prime in exon 8, encoding residues 438-442 (pro-thr-pro-his-pro). In affected members from 6 families with … (more)
The gene for 1-alpha hydroxylase contains a duplicated sequence 5-prime-CCCACCC CCCACCC-3-prime in exon 8, encoding residues 438-442 (pro-thr-pro-his-pro). In affected members from 6 families with vitamin D-dependent rickets type I (264700), Wang et al. (1998) found 3 rather than 2 copies of the 7-bp sequence, which altered the downstream reading frame and created a premature stop signal at codon 446. As this change is upstream from the heme thiolate cysteine at codon 455, the resulting truncated protein is devoid of activity. Families were of diverse ethnic origin (Filipino, Polish, Chinese, white (US), black (US), Hispanic) and several different haplotypes were observed as the background for the mutations. The findings suggested that the 7-bp duplication had arisen by several independent de novo events, indicating a hotspot. (less)
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Pathogenic
(Feb 05, 2020)
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no assertion criteria provided
Method: clinical testing
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Vitamin D-dependent rickets, type 1A
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001190804.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Does Genotype-Phenotype Correlation Exist in Vitamin D-Dependent Rickets Type IA: Report of 13 New Cases and Review of the Literature. | Kaygusuz SB | Calcified tissue international | 2021 | PMID: 33386952 |
Clinical and genetic analysis of two Chinese families with vitamin D-dependent rickets type IA and follow-up. | Li Y | Orphanet journal of rare diseases | 2020 | PMID: 33004071 |
Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A. | Dursun F | Journal of clinical research in pediatric endocrinology | 2019 | PMID: 30282619 |
First Australian report of vitamin D-dependent rickets type I. | Ito N | The Medical journal of Australia | 2014 | PMID: 25296067 |
Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. | Durmaz E | Clinical endocrinology | 2012 | PMID: 22443290 |
Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. | Wang JT | American journal of human genetics | 1998 | PMID: 9837822 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP27B1 | - | - | - | - |
Text-mined citations for rs780950819 ...
HelpRecord last updated Jul 07, 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.