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

Clinical significance:Likely pathogenic (Last evaluated: Aug 24, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000056144.4

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; Cerebrotendinous Xanthomatosis
Identifiers:
MONDO: MONDO:0008948; MedGen: C0238052; Orphanet: 909; OMIM: 213700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000087225GeneReviewsno assertion criteria providedpathologic
(Aug 1, 2013)
not providedcuration

SCV000797944Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 15, 2018)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001382860Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 24, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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

Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis.

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

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

PubMed [citation]
PMID:
10775536
See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000087225.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Counsyl, SCV000797944.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001382860.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces lysine with arginine at codon 259 of the CYP27A1 protein (p.Lys259Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs72551317, ExAC 0.003%). This variant has been observed in several individuals affected with cerebrotendinous xanthomatosis (PMID: 10775536, 22878431). ClinVar contains an entry for this variant (Variation ID: 65898). This variant is also known as p.Lys226Arg in the literature. This variant has been reported not to substantially affect CYP27A1 protein function (PMID: 17697869). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2021

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