NM_000784.4(CYP27A1):c.435G>T (p.Gly145=) AND Cholestanol storage disease

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Mar 14, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000056114.16

Allele description [Variation Report for NM_000784.4(CYP27A1):c.435G>T (p.Gly145=)]

NM_000784.4(CYP27A1):c.435G>T (p.Gly145=)

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.435G>T (p.Gly145=)

HGVS:

NC_000002.12:g.218809756G>T
NG_007959.1:g.33008G>T
NM_000784.4:c.435G>TMANE SELECT
NP_000775.1:p.Gly145=
NC_000002.11:g.219674479G>T
NM_000784.3:c.435G>T

Nucleotide change:

c.435G>T

Links:

dbSNP: rs587778796

NCBI 1000 Genomes Browser:

rs587778796

Molecular consequence:

NM_000784.4:c.435G>T - synonymous variant - [Sequence Ontology: SO:0001819]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000087192	GeneReviews	no assertion criteria provided	pathologic (Aug 1, 2013)	not provided	curation
SCV000267283	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 9521761, 25741868
SCV000800527	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 9, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9521761, 26643207 Citation Link,
SCV000939588	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29321515, 9521761, 28492532
SCV001162937	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001455782	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing

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
not provided	unknown	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
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~60,000 human exomes.

Appadurai V, DeBarber A, Chiang PW, Patel SB, Steiner RD, Tyler C, Bonnen PE.

Mol Genet Metab. 2015 Dec;116(4):298-304. doi: 10.1016/j.ymgme.2015.10.010. Epub 2015 Oct 26.

PubMed [citation]

PMID:: 26643207
PMCID:: PMC4767010

Nationwide survey on cerebrotendinous xanthomatosis in Japan.

Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y.

J Hum Genet. 2018 Mar;63(3):271-280. doi: 10.1038/s10038-017-0389-4. Epub 2018 Jan 10.

PubMed [citation]

PMID:: 29321515

See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000087192.1

#	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 Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (2)

#	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		1	not provided	not provided	not provided

From Counsyl, SCV000800527.1

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

#	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, SCV000939588.6

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

Description

This sequence change affects codon 145 of the CYP27A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYP27A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587778796, gnomAD 0.04%). This variant has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 9521761, 29321515). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly112Gly. ClinVar contains an entry for this variant (Variation ID: 65869). Studies have shown that this variant results in alternative splicing and introduces a premature termination codon (PMID: 9521761). The resulting mRNA is expected to undergo nonsense-mediated decay. 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, SCV001162937.2

#	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

From Natera, Inc., SCV001455782.1

#	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

Last Updated: Jun 17, 2024

ClinVar

Relating variation to medicine