VCV000282791.53 - ClinVar

NM_000784.4(CYP27A1):c.1471G>T (p.Ala491Ser)

Germline

Classification

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.

(13)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000784.4(CYP27A1):c.1471G>T (p.Ala491Ser)

Variation ID: 282791 Accession: VCV000282791.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218814752 (GRCh38) [ NCBI UCSC ] 2: 219679475 (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 6, 2016	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000784.4:c.1471G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000775.1:p.Ala491Ser	missense
NC_000002.12:g.218814752G>T
NC_000002.11:g.219679475G>T
NG_007959.1:g.38004G>T

Protein change

A491S

Other names

Canonical SPDI

NC_000002.12:218814751:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00120 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00120

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00138

1000 Genomes Project 30x 0.00141

Trans-Omics for Precision Medicine (TOPMed) 0.00154

Links

ClinGen: CA2112901 dbSNP: rs72551323 VarSome

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
Gene	OMIM	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.
CYP27A1		-	-	GRCh38 GRCh37	1097	1129

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.
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV000512745.30
Cholestanol storage disease	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000611602.18
not specified	Benign (2)	criteria provided, single submitter	Aug 26, 2015	RCV000373347.7
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Sep 7, 2023	RCV003372675.2
CYP27A1-related disorder	Benign (1)	no assertion criteria provided	May 10, 2019	RCV003930067.2

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.
Likely benign (Mar 02, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Cholestanol storage disease Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744175.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (May 15, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000843001.1 First in ClinVar: Oct 30, 2017 Last updated: Oct 30, 2017
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cholestanol storage disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001122558.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Aug 26, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000334436.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP27A1 Number of individuals with the variant: 1 Sex: mixed
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cholestanol storage disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001298665.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 24584636 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Feb 09, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001803088.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (Sep 07, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004096009.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000609024.31 First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024	Comment: CYP27A1: BP4 Number of individuals with the variant: 5
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924907.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (May 10, 2019)	no assertion criteria provided Method: clinical testing	CYP27A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004740714.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Benign (-)	no assertion criteria provided Method: clinical testing	Cholestanol storage disease Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734172.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Likely benign (Jun 12, 2020)	no assertion criteria provided Method: clinical testing	Cerebrotendinous xanthomatosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462727.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036938.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cerebrotendinous xanthomatosis: recurrence of the CYP27A1 mutation p.Arg479Cys in Sardinia.	Mandrile G	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2014	PMID: 24584636
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP27A1	-	-	-	-

Text-mined citations for rs72551323 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000784.4(CYP27A1):c.1471G>T (p.Ala491Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72551323 ...