ClinVar Genomic variation as it relates to human health
NM_000784.4(CYP27A1):c.646G>C (p.Ala216Pro)
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_000784.4(CYP27A1):c.646G>C (p.Ala216Pro)
Variation ID: 65885 Accession: VCV000065885.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218812421 (GRCh38) [ NCBI UCSC ] 2: 219677144 (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 1, 2013 Mar 16, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000784.4:c.646G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000775.1:p.Ala216Pro missense NC_000002.12:g.218812421G>C NC_000002.11:g.219677144G>C NG_007959.1:g.35673G>C - Protein change
- A216P
- Other names
- c.646G>C
- Canonical SPDI
- NC_000002.12:218812420:G:C
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
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 | ||
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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 |
1068 | 1099 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000056130.12 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV001268441.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV003964910.1 |
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
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447376.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cerebellar ataxia (present) , Intellectual disability (present) , Spasticity (present) , Spastic paraplegia (present) , Gait disturbance (present) , Lower limb spasticity (present) , Progressive … (more)
Cerebellar ataxia (present) , Intellectual disability (present) , Spasticity (present) , Spastic paraplegia (present) , Gait disturbance (present) , Lower limb spasticity (present) , Progressive spasticity (present) (less)
Sex: male
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Pathogenic
(Sep 13, 2021)
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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: SCV001983522.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: CYP27A1 c.646G>C (p.Ala216Pro) 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.646G>C (p.Ala216Pro) 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 is located at the last nucleotide of exon 3. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Four predict the variant abolishes a 3' acceptor site. Experimental studies report this variant to affect mRNA splicing (Garuti_1996). The variant allele was found at a frequency of 3.2e-05 in 251286 control chromosomes. c.646G>C has been reported in the literature in numerous individuals affected with Cerebrotendinous Xanthomatosis both in the homozygous and compound heterozygous state (Garuti_1996, Bartholdi_2004, Ginanneschi_2013, etc). Experimental studies performed on fibroblasts from an individual homozygous for the variant showed a negligible or a very low residual activity compared to controls (Garuti_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 14, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002776778.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 25, 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: SCV004192675.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502385.16
First in ClinVar: Mar 14, 2021 Last updated: Mar 10, 2024 |
Comment:
CYP27A1: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Jan 17, 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: SCV001229364.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 216 of the CYP27A1 protein (p.Ala216Pro). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 216 of the CYP27A1 protein (p.Ala216Pro). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201346271, gnomAD 0.006%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 8827518, 10775536, 14999499, 24746394). This variant is also known as p.Ala183Pro. ClinVar contains an entry for this variant (Variation ID: 65885). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters CYP27A1 gene expression (PMID: 8827518). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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CYP27A1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004781174.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CYP27A1 c.646G>C variant is predicted to result in the amino acid substitution p.Ala216Pro. This variant is also referred to as p.Ala183Pro in literature. This … (more)
The CYP27A1 c.646G>C variant is predicted to result in the amino acid substitution p.Ala216Pro. This variant is also referred to as p.Ala183Pro in literature. This variant has been reported in the homozygous state and along with another variant in CYP27A1 in multiple individuals with cerebrotendinous xanthomatosis (Garuti et al. 1996. PubMed ID: 8827518, Gupta et al. 2007. PubMed ID: 17697869; Verrips et al. 2000. PubMed ID: 10775536). Splicing analysis found this variant results in aberrant splicing and reduced mRNA levels (Garuti et al. 1996. PubMed ID: 8827518; Gupta et al. 2007. PubMed ID: 17697869). This variant is interpreted as pathogenic. (less)
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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: SCV000087208.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917630.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cerebrotendinous xanthomatosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455784.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930560.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956543.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Cerebrotendinous Xanthomatosis. | Adam MP | - | 2022 | PMID: 20301583 |
[Cerebrotendinous xanthomatosis: a multicentric retrospective study of 15 adults, clinical and paraclinical typical and atypical aspects]. | Lionnet C | Revue neurologique | 2014 | PMID: 24746394 |
Polyneuropathy in cerebrotendinous xanthomatosis and response to treatment with chenodeoxycholic acid. | Ginanneschi F | Journal of neurology | 2013 | PMID: 22878431 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Spinal phenotype of cerebrotendinous xanthomatosis--a pitfall in the diagnosis of multiple sclerosis. | Bartholdi D | Journal of neurology | 2004 | PMID: 14999499 |
Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. | Verrips A | Brain : a journal of neurology | 2000 | PMID: 10775536 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Cerebrotendinous xanthomatosis caused by two new mutations of the sterol-27-hydroxylase gene that disrupt mRNA splicing. | Garuti R | Journal of lipid research | 1996 | PMID: 8827518 |
Text-mined citations for rs201346271 ...
HelpRecord last updated Mar 17, 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.