NM_000784.4(CYP27A1):c.1180_1181del (p.Leu394fs) AND Cholestanol storage disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 26, 2023
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:: RCV000674414.13

Allele description [Variation Report for NM_000784.4(CYP27A1):c.1180_1181del (p.Leu394fs)]

NM_000784.4(CYP27A1):c.1180_1181del (p.Leu394fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_000784.4(CYP27A1):c.1180_1181del (p.Leu394fs)

HGVS:

NC_000002.12:g.218814181CT[1]
NG_007959.1:g.37433CT[1]
NM_000784.4:c.1180_1181delMANE SELECT
NP_000775.1:p.Leu394fs
NC_000002.11:g.219678904CT[1]
NC_000002.11:g.219678904_219678905del
NM_000784.3:c.1180_1181del
NM_000784.3:c.1180_1181delCT

Protein change:

L394fs

Links:

dbSNP: rs1178393503

NCBI 1000 Genomes Browser:

rs1178393503

Molecular consequence:

NM_000784.4:c.1180_1181del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000799747	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 3, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001381317	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11181744, 9392430, 10775536, 26937392, 28492532
SCV002078801	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 30, 2020)	germline	clinical testing
SCV004192665	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.

Lee MH, Hazard S, Carpten JD, Yi S, Cohen J, Gerhardt GT, Salen G, Patel SB.

J Lipid Res. 2001 Feb;42(2):159-69.

PubMed [citation]

PMID:: 11181744
PMCID:: PMC1418947

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 (6)

Details of each submission

From Counsyl, SCV000799747.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001381317.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 558186). This variant is also known as Ex6Œî2bp. This premature translational stop signal has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 11181744). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Leu394Alafs*18) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392).

#	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 Natera, Inc., SCV002078801.1

#	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 Baylor Genetics, SCV004192665.1

#	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

Last Updated: Sep 29, 2024

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