ClinVar Genomic variation as it relates to human health
NM_000784.4(CYP27A1):c.1435C>G (p.Arg479Gly)
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.
Pathogenic(4); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000784.4(CYP27A1):c.1435C>G (p.Arg479Gly)
Variation ID: 4267 Accession: VCV000004267.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218814716 (GRCh38) [ NCBI UCSC ] 2: 219679439 (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 Apr 4, 2013 Apr 15, 2024 Feb 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000784.4:c.1435C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000775.1:p.Arg479Gly missense NC_000002.12:g.218814716C>G NC_000002.11:g.219679439C>G NG_007959.1:g.37968C>G - Protein change
- R479G
- Other names
- c.1435C>G
- Canonical SPDI
- NC_000002.12:218814715:C:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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
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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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CYP27A1 | - | - |
GRCh38 GRCh37 |
1081 | 1111 |
Conditions - Germline
Condition
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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
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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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2024 | RCV000004488.11 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 11, 2022 | RCV000597433.8 |
Submissions - Germline
Classification
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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
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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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Uncertain significance
(May 08, 2017)
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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: SCV000708128.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Feb 11, 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: SCV002104322.2
First in ClinVar: Mar 19, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32344004, 22878431, 25112387, 23115103, 16278884, 27225395, 16816916, 26643207, 33830582, 21764626) (less)
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Pathogenic
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cholestanol storage disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004192659.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cholestanol storage disease
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238135.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cholestanol storage disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003525195.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 479 of the CYP27A1 protein (p.Arg479Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 479 of the CYP27A1 protein (p.Arg479Gly). This variant is present in population databases (rs72551322, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of cerebrotendinous xanthomatosis (PMID: 16278884, 25112387). 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: 4267). 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 CYP27A1 protein function. This variant disrupts the p.Arg479 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2019602, 21073839, 24584636). 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)
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Pathogenic
(Feb 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cholestanol storage disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015195.2
First in ClinVar: Nov 20, 2021 Last updated: Apr 15, 2024 |
Comment:
Variant summary: CYP27A1 c.1435C>G (p.Arg479Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CYP27A1 c.1435C>G (p.Arg479Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250796 control chromosomes. c.1435C>G has been reported in the literature in homozygous or compound heterozygous individuals or heterozygous individual without a reported second variant, all affected with Cerebrotendinous Xanthomatosis (e.g. Guyant-Marechal_2005, Mignarri_2012, Saute_2015, Di Taranto_2016, Fussinger_2022). These data indicate that the variant is likely to be associated with disease. A different variant located at the same codon (c.1435C>T, p.Arg479Cys) has been classified as pathogenic by our lab, with ClinVar providing additional pathogenic classifications for variants at this position, supporting a critical relevance of this residue to CYP27A1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33830582, 27225395, 16278884, 21764626, 25112387, 36537231). ClinVar contains an entry for this variant (Variation ID: 4267). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cholestanol storage disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000799827.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
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pathologic
(Aug 01, 2013)
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no assertion criteria provided
Method: curation
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Cerebrotendinous Xanthomatosis
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000087162.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554136.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CYP27A1 p.Arg479Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP … (more)
The CYP27A1 p.Arg479Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs72551322) as “With Pathogenic allele”. The variant was identified in ClinVar with conflicting interpretations of pathogenicity, with submissions of likely pathogenic (Counsyl), pathogenic (OMIM and GeneReviews), and uncertain significance (EGL Genetics Diagnostics). The associated condition is cholesterol storage disease. The variant was identified in control databases in 4 of 282188 chromosomes at a frequency of 0.000014 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 35424 chromosomes (freq: 0.000028) and European (non-Finnish) in 3 of 128792 chromosomes (freq: 0.000023); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. This variant was identified as a causal homozygous variant in a patient with Cerebrotendinous xanthomatosis and was identified in another case study in the compound heterozygous state in a patient with unusual Cerebrotendinous xanthomatosis with fronto-temporal dementia (Di Taranto_2016_PMID:27225395; Guyant-Marechal_2005_PMID:16278884). The variant occurs outside of the splicing consensus sequence and four out of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a greater than 10% difference in splicing. The p.Arg479 residue is conserved in mammals but not more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, and MutationTaster) suggest that the variant may impact the protein. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. (less)
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Pathogenic
(Dec 01, 2005)
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no assertion criteria provided
Method: literature only
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CEREBROTENDINOUS XANTHOMATOSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024662.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2024 |
Comment on evidence:
For discussion of the 1435C-G transversion in exon 8 of the CYP27A1 gene, resulting in an arg479-to-gly (R479G) substitution, that was found in compound heterozygous … (more)
For discussion of the 1435C-G transversion in exon 8 of the CYP27A1 gene, resulting in an arg479-to-gly (R479G) substitution, that was found in compound heterozygous state in a patient with cerebrotendinous xanthomatosis by Guyant-Marechal et al. (2005), see 606530.0013. (less)
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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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Copy number variations in SPAST and ATL1 are rare among Brazilians. | Fussiger H | Clinical genetics | 2023 | PMID: 36537231 |
Cerebrotendinous Xanthomatosis. | Adam MP | - | 2022 | PMID: 20301583 |
Cerebrotendinous xanthomatosis without neurological involvement. | Stelten BML | Journal of internal medicine | 2021 | PMID: 33830582 |
Cerebrotendinous xanthomatosis, a metabolic disease with different neurological signs: two case reports. | Di Taranto MD | Metabolic brain disease | 2016 | PMID: 27225395 |
Look carefully to the heels! A potentially treatable cause of spastic paraplegia. | Saute JA | Journal of inherited metabolic disease | 2015 | PMID: 25112387 |
Parkinsonism as neurological presentation of late-onset cerebrotendinous xanthomatosis. | Mignarri A | Parkinsonism & related disorders | 2012 | PMID: 21764626 |
Clinical imaging and neuropathological correlations in an unusual case of cerebrotendinous xanthomatosis. | Wallon D | Clinical neuropathology | 2010 | PMID: 21073839 |
Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype. | Guyant-Maréchal L | American journal of medical genetics. Part A | 2005 | PMID: 16278884 |
Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. | Cali JJ | The Journal of biological chemistry | 1991 | PMID: 2019602 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP27A1 | - | - | - | - |
Text-mined citations for rs72551322 ...
HelpRecord last updated Apr 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.