NM_000784.4(CYP27A1):c.845-1G>A AND Cholestanol storage disease

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 12, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004478.18

Allele description [Variation Report for NM_000784.4(CYP27A1):c.845-1G>A]

NM_000784.4(CYP27A1):c.845-1G>A

Gene:

CYP27A1:cytochrome P450 family 27 subfamily A member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_000784.4(CYP27A1):c.845-1G>A

HGVS:

NC_000002.12:g.218812923G>A
NG_007959.1:g.36175G>A
NM_000784.4:c.845-1G>AMANE SELECT
NC_000002.11:g.219677646G>A
NM_000784.3:c.845-1G>A

Nucleotide change:

c.845-1G>A

Links:

OMIM: 606530.0003; dbSNP: rs397515353

NCBI 1000 Genomes Browser:

rs397515353

Molecular consequence:

NM_000784.4:c.845-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Cholestanol storage disease (CTX)
Synonyms:: Cerebral cholesterinosis; CTX: Cerebrotendinous xanthomatosis; Cerebrotendinous Xanthomatosis
Identifiers:: MONDO: MONDO:0008948; MedGen: C0238052; Orphanet: 909; OMIM: 213700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024651	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000087233	GeneReviews	no assertion criteria provided	pathologic (Aug 1, 2013)	not provided	curation
SCV001588697	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16199547, 9392430, 10775536, 26937392, 8514861, 21645175, 27084087, 28492532
SCV002060344	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Pathogenic (Nov 9, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21404287, 27084087, 8514861 Citation Link,
SCV002078786	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 26, 2017)	germline	clinical testing
SCV002780601	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 27, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004192652	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 12, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Four novel mutations of sterol 27-hydroxylase gene in Italian patients with cerebrotendinous xanthomatosis.

Garuti R, Croce MA, Tiozzo R, Dotti MT, Federico A, Bertolini S, Calandra S.

J Lipid Res. 1997 Nov;38(11):2322-34.

PubMed [citation]

PMID:: 9392430

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000024651.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

A relatively high prevalence of cerebrotendinous xanthomatosis (CTX; 213700) has been noted in Jews of Moroccan origin. By single-strand conformation polymorphism analysis followed by sequence analysis, Leitersdorf et al. (1993) identified 2 mutations in the CYP27A1 gene in affected members of 4 families. One mutation was deletion of a thymidine in exon 4 that resulted in frameshift and premature termination 35 nucleotides downstream. The other was a G-to-A transition at the 3-prime splice acceptor site of intron 4 (606530.0004). Two patients from 2 families were homozygous for the frameshift. In 4 families that were studied, 1 was homozygous for the splice mutation, 2 were homozygous for the frameshift mutation, and 1 was a genetic compound for the 2 mutations. Only the fourth family was nonconsanguineous.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000087233.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

Converted during submission to Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001588697.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change affects an acceptor splice site in intron 4 of the CYP27A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). This variant is present in population databases (rs397515353, gnomAD 0.1%). Disruption of this splice site has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 8514861, 21645175, 27084087). ClinVar contains an entry for this variant (Variation ID: 4256). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060344.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

NM_000784.3(CYP27A1):c.845-1G>A is a canonical splice variant classified as pathogenic in the context of cerebrotendinous xanthomatosis. c.845-1G>A has been observed in cases with relevant disease (PMID: 27084087, 21404287, 8514861). Functional assessments of this variant are available in the literature (PMID: 8514861). c.845-1G>A has been observed in population frequency databases (gnomAD: ASJ 0.11%). In summary, NM_000784.3(CYP27A1):c.845-1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002078786.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002780601.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004192652.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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