VCV000498357.29 - ClinVar

NM_000784.4(CYP27A1):c.491G>C (p.Arg164Pro)

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.

(12)

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.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000784.4(CYP27A1):c.491G>C (p.Arg164Pro)

Variation ID: 498357 Accession: VCV000498357.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218812266 (GRCh38) [ NCBI UCSC ] 2: 219676989 (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 15, 2018	Oct 8, 2024	May 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000784.4:c.491G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000775.1:p.Arg164Pro	missense
NC_000002.12:g.218812266G>C
NC_000002.11:g.219676989G>C
NG_007959.1:g.35518G>C

Protein change

R164P

Other names

p.Arg164Pro

Canonical SPDI

NC_000002.12:218812265:G:C

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00007

Links

ClinGen: CA2112625 dbSNP: rs148417330 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	1099	1131

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	Uncertain significance (7)	criteria provided, multiple submitters, no conflicts	Feb 21, 2024	RCV000594613.16
Cholestanol storage disease	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000765608.13
CYP27A1-related disorder	Uncertain significance (1)	no assertion criteria provided	Aug 30, 2024	RCV003420031.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	May 8, 2024	RCV004024736.2

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.
Uncertain significance (Jun 05, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703336.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	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: 8 Sex: mixed
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholestanol storage disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896931.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Aug 11, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001476715.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (1) PubMed: 30366773
Uncertain significance (Jan 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004225985.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Number of individuals with the variant: 1
Likely 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: SCV001197285.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024
Uncertain significance (May 08, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003949920.3 First in ClinVar: Jul 08, 2023 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 30366773 Comment: The c.491G>C (p.R164P) alteration is located in exon 3 (coding exon 3) of the CYP27A1 gene. This alteration results from a G to C substitution … (more) The c.491G>C (p.R164P) alteration is located in exon 3 (coding exon 3) of the CYP27A1 gene. This alteration results from a G to C substitution at nucleotide position 491, causing the arginine (R) at amino acid position 164 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 21, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002513641.4 First in ClinVar: May 21, 2022 Last updated: Sep 29, 2024	Comment: Reported as a heterozygous variant in a patient with an inborn error of bile acid metabolism in the published literature; however, a second variant in … (more) Reported as a heterozygous variant in a patient with an inborn error of bile acid metabolism in the published literature; however, a second variant in CYP27A1 was not reported (PMID: 30366773); 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: 30366773) (less)
Uncertain significance (Jan 17, 2020)	no assertion criteria provided Method: clinical testing	Cerebrotendinous xanthomatosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462715.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001978891.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980364.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Uncertain significance (-)	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: SCV002035703.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Uncertain significance (Aug 30, 2024)	no assertion criteria provided Method: clinical testing	CYP27A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004116631.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The CYP27A1 c.491G>C variant is predicted to result in the amino acid substitution p.Arg164Pro. This variant has been reported in a patient with an inborn … (more) The CYP27A1 c.491G>C variant is predicted to result in the amino acid substitution p.Arg164Pro. This variant has been reported in a patient with an inborn error of bile acid metabolism; however, this patient lacked a second variant in CYP27A1 and also had a homozygous variant in the AKR1D1 gene and a heterozygous variant in the ABCC3 gene (Patient 04 in Table 4, Chen et al 2018. PubMed ID: 30366773). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD, which may be too common for a pathogenic variant. This variant has conflicting interpretations in ClinVar regarding its pathogenicity ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/498357). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

The c.491G>C (p.R164P) alteration is located in exon 3 (coding exon 3) of the CYP27A1 gene. This alteration results from a G to C substitution at nucleotide position 491, causing the arginine (R) at amino acid position 164 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Reported as a heterozygous variant in a patient with an inborn error of bile acid metabolism in the published literature; however, a second variant in CYP27A1 was not reported (PMID: 30366773); 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: 30366773)

Comment:

The CYP27A1 c.491G>C variant is predicted to result in the amino acid substitution p.Arg164Pro. This variant has been reported in a patient with an inborn error of bile acid metabolism; however, this patient lacked a second variant in CYP27A1 and also had a homozygous variant in the AKR1D1 gene and a heterozygous variant in the ABCC3 gene (Patient 04 in Table 4, Chen et al 2018. PubMed ID: 30366773). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD, which may be too common for a pathogenic variant. This variant has conflicting interpretations in ClinVar regarding its pathogenicity ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/498357). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges.	Chen HL	The Journal of pediatrics	2019	PMID: 30366773
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP27A1	-	-	-	-

Text-mined citations for rs148417330 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000784.4(CYP27A1):c.491G>C (p.Arg164Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148417330 ...