NM_000784.4(CYP27A1):c.776A>G (p.Lys259Arg) AND Cholestanol storage disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 10, 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:: RCV000056144.9

Allele description [Variation Report for NM_000784.4(CYP27A1):c.776A>G (p.Lys259Arg)]

NM_000784.4(CYP27A1):c.776A>G (p.Lys259Arg)

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.776A>G (p.Lys259Arg)

HGVS:

NC_000002.12:g.218812681A>G
NG_007959.1:g.35933A>G
NM_000784.4:c.776A>GMANE SELECT
NP_000775.1:p.Lys259Arg
NC_000002.11:g.219677404A>G
NM_000784.3:c.776A>G

Nucleotide change:

c.776A>G

Protein change:

K259R

Links:

dbSNP: rs72551317

NCBI 1000 Genomes Browser:

rs72551317

Molecular consequence:

NM_000784.4:c.776A>G - 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
SCV000087225	GeneReviews	no assertion criteria provided	pathologic (Aug 1, 2013)	not provided	curation
SCV000797944	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 15, 2018)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10775536, 22878431, 17697869, 11181744 Citation Link,
SCV001382860	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10775536, 22878431, 17697869, 28492532
SCV004192678	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 21, 2023)	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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

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

Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis.

Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ, van Engelen BG, van den Heuvel LP.

Brain. 2000 May;123 ( Pt 5):908-19.

PubMed [citation]

PMID:: 10775536

See all PubMed Citations (6)

Details of each submission

From GeneReviews, SCV000087225.1

#	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 Counsyl, SCV000797944.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	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 Invitae, SCV001382860.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 259 of the CYP27A1 protein (p.Lys259Arg). This variant is present in population databases (rs72551317, gnomAD 0.005%). This missense change has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 10775536, 22878431). This variant is also known as p.Lys226Arg. ClinVar contains an entry for this variant (Variation ID: 65898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP27A1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect CYP27A1 function (PMID: 17697869). 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 Baylor Genetics, SCV004192678.1

#	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: Apr 15, 2024

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