NM_000784.4(CYP27A1):c.425T>C (p.Leu142Pro) AND Cholestanol storage disease

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 22, 2022
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:: RCV000792745.7

Allele description [Variation Report for NM_000784.4(CYP27A1):c.425T>C (p.Leu142Pro)]

NM_000784.4(CYP27A1):c.425T>C (p.Leu142Pro)

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.425T>C (p.Leu142Pro)

HGVS:

NC_000002.12:g.218809746T>C
NG_007959.1:g.32998T>C
NM_000784.4:c.425T>CMANE SELECT
NP_000775.1:p.Leu142Pro
NC_000002.11:g.219674469T>C
NM_000784.3:c.425T>C

Protein change:

L142P

Links:

dbSNP: rs369363177

NCBI 1000 Genomes Browser:

rs369363177

Molecular consequence:

NM_000784.4:c.425T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000932061	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21955034, 28492532
SCV001462714	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jan 4, 2020)	germline	clinical testing
SCV003830395	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000932061

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 22, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001462714

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jan 4, 2020)

germline

clinical testing

SCV003830395

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 29, 2021)

germline

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Extreme xanthomatosis in patients with both familial hypercholesterolemia and cerebrotendinous xanthomatosis.

Huijgen R, Stork AD, Defesche JC, Peter J, Alonso R, Cuevas A, Kastelein JJ, Duran M, Stroes ES.

Clin Genet. 2012 Jan;81(1):24-8. doi: 10.1111/j.1399-0004.2011.01793.x. Epub 2011 Oct 16.

PubMed [citation]

PMID:: 21955034

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000932061.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 142 of the CYP27A1 protein (p.Leu142Pro). This variant is present in population databases (rs369363177, gnomAD 0.02%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 21955034). ClinVar contains an entry for this variant (Variation ID: 639836). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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., SCV001462714.1

#	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 Revvity Omics, Revvity, SCV003830395.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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