VCV000065869.17 - ClinVar

NM_000784.4(CYP27A1):c.435G>T (p.Gly145=)

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.

(7)

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/Likely pathogenic

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.435G>T (p.Gly145=)

Variation ID: 65869 Accession: VCV000065869.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218809756 (GRCh38) [ NCBI UCSC ] 2: 219674479 (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	Oct 1, 2013	Oct 8, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000784.4:c.435G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000775.1:p.Gly145=	synonymous
NC_000002.12:g.218809756G>T
NC_000002.11:g.219674479G>T
NG_007959.1:g.33008G>T

Protein change

Other names

c.435G>T

Canonical SPDI

NC_000002.12:218809755: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.

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA345201 dbSNP: rs587778796 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.
Cholestanol storage disease	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000056114.17
CYP27A1-related disorder	Likely pathogenic (1)	no assertion criteria provided	Feb 14, 2024	RCV003915020.2

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 pathogenic (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Cholestanol storage disease Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267283.1 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013	Publications: PubMed (1) PubMed: 9521761 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholestanol storage disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162937.2 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (Oct 22, 2023)	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: SCV000939588.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 9521761‚ 29321515 Comment: This sequence change affects codon 145 of the CYP27A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 145 of the CYP27A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYP27A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587778796, gnomAD 0.04%). This variant has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 9521761, 29321515). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly112Gly. ClinVar contains an entry for this variant (Variation ID: 65869). Studies have shown that this variant results in alternative splicing and introduces a premature termination codon (PMID: 9521761). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
pathologic (Aug 01, 2013)	no assertion criteria provided Method: curation	Cerebrotendinous Xanthomatosis Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000087192.1 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013	Comment: Converted during submission to Pathogenic.
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Cerebrotendinous xanthomatosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001455782.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely pathogenic (Feb 14, 2024)	no assertion criteria provided Method: clinical testing	CYP27A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004727954.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The CYP27A1 c.435G>T variant is not predicted to result in an amino acid change (p.=). This variant is predicted to alter splicing based on available … (more) The CYP27A1 c.435G>T variant is not predicted to result in an amino acid change (p.=). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751) and a RT-PCR study showed this variant impacts mRNA splicing leading to a cryptic GT Donor site (Figure 5, Chen et al. 1998. PubMed ID: 9521761). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with cerebrotendinous xanthomatosis (Figure 5, Chen et al. 1998. PubMed ID: 9521761; Figure 2, Tang et al. 2020. PubMed ID: 31914338; Figure 1, Cao et al. 2020. PubMed ID: 33269283). This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD. It has also been described as one of the most common variants observed in Japanese individuals with cerebrotendinous xanthomatosis (Sekijima et al. 2018. PubMed ID: 29321515). This variant is interpreted as likely pathogenic. (less)
Uncertain significance (May 09, 2017)	Flagged submission flagged submission (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Cholestanol storage disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800527.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Publications: PubMed (2) PubMed: 9521761‚ 26643207
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This sequence change affects codon 145 of the CYP27A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYP27A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587778796, gnomAD 0.04%). This variant has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 9521761, 29321515). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly112Gly. ClinVar contains an entry for this variant (Variation ID: 65869). Studies have shown that this variant results in alternative splicing and introduces a premature termination codon (PMID: 9521761). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The CYP27A1 c.435G>T variant is not predicted to result in an amino acid change (p.=). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751) and a RT-PCR study showed this variant impacts mRNA splicing leading to a cryptic GT Donor site (Figure 5, Chen et al. 1998. PubMed ID: 9521761). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with cerebrotendinous xanthomatosis (Figure 5, Chen et al. 1998. PubMed ID: 9521761; Figure 2, Tang et al. 2020. PubMed ID: 31914338; Figure 1, Cao et al. 2020. PubMed ID: 33269283). This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD. It has also been described as one of the most common variants observed in Japanese individuals with cerebrotendinous xanthomatosis (Sekijima et al. 2018. PubMed ID: 29321515). This variant is interpreted as likely pathogenic.

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.	Adam MP	-	2024	PMID: 20301583
Nationwide survey on cerebrotendinous xanthomatosis in Japan.	Sekijima Y	Journal of human genetics	2018	PMID: 29321515
Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~60,000 human exomes.	Appadurai V	Molecular genetics and metabolism	2015	PMID: 26643207
A novel Arg362Ser mutation in the sterol 27-hydroxylase gene (CYP27): its effects on pre-mRNA splicing and enzyme activity.	Chen W	Biochemistry	1998	PMID: 9790667
Silent nucleotide substitution in the sterol 27-hydroxylase gene (CYP 27) leads to alternative pre-mRNA splicing by activating a cryptic 5' splice site at the mutant codon in cerebrotendinous xanthomatosis patients.	Chen W	Biochemistry	1998	PMID: 9521761

Text-mined citations for rs587778796 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000784.4(CYP27A1):c.435G>T (p.Gly145=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778796 ...