2-218814186-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000784.4(CYP27A1):c.1183C>T(p.Arg395Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 missense, splice_region

Scores

Splicing: ADA: 0.9911

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23U:1O:1

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 2-218814186-C-T is Pathogenic according to our data. Variant chr2-218814186-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218814186-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4 link	c.1183C>T	p.Arg395Cys	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000258415.9	NP_000775.1	Q02318

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9 link	c.1183C>T	p.Arg395Cys	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_000784.4	ENSP00000258415.4		Q02318
CYP27A1	ENST00000494263.5 link	n.1617C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000287

AC:

AN:

251236

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000438

AC:

640

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

304

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000528

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000289

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000339

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:14Other:1

Jul 12, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP3 supporting -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000784.3(CYP27A1):c.1183C>T(R395C) is classified as pathogenic in the context of cerebrotendinous xanthomatosis. Sources cited for classification include the following: PMID 2019602, 10775536, 21955034 and 21645175. Classification of NM_000784.3(CYP27A1):c.1183C>T(R395C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 395 of the CYP27A1 protein (p.Arg395Cys). This variant is present in population databases (rs121908096, gnomAD 0.05%). This missense change has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 2019602, 10775536, 18227423, 20402754, 21645175, 21955034, 24746394, 26156051, 26906304). This variant is also known as p.Arg362Cys. ClinVar contains an entry for this variant (Variation ID: 4255). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYP27A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP27A1 function (PMID: 2019602). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg395 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8950197, 9790667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cerebrotendinous xanthomatosis (MIM#213700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. This variant is also in a splice region (second last coding base of exon 6), however cDNA studies have shown it does not affect splicing (PMID: 25983621). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (80 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 14 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Cytochrome P450 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic, in either a homozygous or compound heterozygous state, in multiple patients with cerebrotendinous xanthomatosis (ClinVar, PMIDs: 2019602, 21645175, 28324197). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in multiple families (PMIDs: 21645175, 28324197). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells displayed reduced enzyme activity (PMID: 2019602). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 08, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2014

Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This patient is a compound heterozygote for the substitution c.256-1G>T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the pathogenic mutation c.1183C>T(p.Arg395Cys). -

Sep 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYP27A1 c.1183C>T (p.Arg395Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251236 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (0.00029 vs 0.0011), allowing no conclusion about variant significance. c.1183C>T has been reported in the literature in multiple individuals affected with Cerebrotendinous Xanthomatosis (e.g. Degos_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27084087). ClinVar contains an entry for this variant (Variation ID: 4255). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 05, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Israeli Druze [Falik-Zaccai et al 2008] -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the CYP27A1 c.1183C>T (p.Arg395Cys) variant has been reported in nine studies in which is found in a total of 20 individuals with cerebrotendinous xanthomatosis, including four in a homozygous state and 16 in a compound heterozygous state, and in at least 18 additional disease alleles of unknown zygosity (Cali et al. 1991; Verrips et al. 2000; Szlago et al. 2008; Pilo-de-la-Fuente et al. 2011; Lionnet et al. 2014; Smally et al. 2015; Varman et al. 2016; Huidekoper et al. 2016; Koopal et al. 2016). The p.Arg395Cys variant was absent from 310 control alleles but is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies by Cali et al. (1991) showed the p.Arg395Cys variant had no detectable sterol 27-hydroxylase enzyme activity when expressed in COS-M6 cells. Gupta et al. (2007) demonstrated in COS-1 cells that the variant resulted in lower levels of protein expression and disrupted the heme-binding domain, resulting in an inactive protein. Based on the collective evidence, the p.Arg395Cys variant is classified pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 25, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:8

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 21, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM3_strong, PS3, PS4_moderate -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; specifically, in vitro functional studies showed no detectable enzyme activity in cells transfected with R362C cDNA (Cali et al., 1991); Known as R362C according to alternate nomenclature; This variant is associated with the following publications: (PMID: 17697869, 10775536, 10430841, 26906304, 25983621, 12933951, 20402754, no PMID, 2019602, 8931710, 11181744, 21645175, 26156051, 21955034, 24746394, 22849591, 18227423, 28894950, 29260356, 31859899, 31980526, 33659184, 34103343, 34426522, 31589614, 33977023) -

CYP27A1-related disorder

Pathogenic:1

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CYP27A1 c.1183C>T variant is predicted to result in the amino acid substitution p.Arg395Cys. This variant is located within the cytochrome P-450 domain of the protein and has been reported to be causative for autosomal recessive cerebrotendinous xanthomatosis (see for examples Cali et al. 1991. PubMed ID: 2019602 [reported as p.Arg362Cys]; Smalley et al. 2015. PubMed ID: 25983621; Huidekoper et al. 2016. PubMed ID: 26156051). The Cali et al. study also performed a functional assay using transfected mammalian cell cultures that showed the p.Arg395Cys substitution greatly reduced enzymatic activity of the protein (Cali et al. 1991. PubMed ID: 2019602). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4255). Given all the evidence, we too interpret c.1183C>T (p.Arg395Cys) as pathogenic. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MVP

0.98

MPC

0.84

ClinPred

0.60

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over