2-218814186-C-T

Variant names:

• chr2-218814186-C-T
• rs121908096
• NM_000784.4:c.1183C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_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. 14/24 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395H) has been classified 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:24 U:1 O:1
• Conservation: PhyloP100: 1.02
• Publications: 43 publications found

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 Gene-Disease associations (from GenCC):

• cerebrotendinous xanthomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000784.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218814187-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-218814186-C-T is Pathogenic according to our data. Variant chr2-218814186-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.1183C>T	p.Arg395Cys	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000494263.5	n.1617C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2
CYP27A1	ENST00000445971.1	n.*644C>T		downstream_gene_variant		5		ENSP00000404945.1
CYP27A1	ENST00000466602.1	n.*95C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152188 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251236 AF XY: 0.000228

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 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.: 0 Cov.: 31 AF XY: 0.000418 AC XY: 304 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000528 AC: 587 AN: 1111996

Other (OTH) AF: 0.000182 AC: 11 AN: 60394

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74346

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholestanol storage disease Pathogenic:14 Other:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

Apr 25, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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). -

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. -

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. -

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 -

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. -

Sep 05, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:8

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Jun 21, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

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 -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

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. -

Cardiovascular phenotype Pathogenic:1

Dec 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R395C pathogenic mutation (also known as c.1183C>T), located in coding exon 6 of the CYP27A1 gene, results from a C to T substitution at nucleotide position 1183. The arginine at codon 395 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other CYP27A1 variant(s) in individual(s) with features consistent with cerebrotendinous xanthomatosis; in at least one instance, the variants were identified in trans (Cali JJ et al. J Biol Chem, 1991 Apr;266:7779-83; Verrips A et al. Brain, 2000 May;123 ( Pt 5):908-19; Castelnovo G et al. J Neurol Neurosurg Psychiatry, 2003 Sep;74:1335; Lorincz MT et al. Arch Neurol, 2005 Sep;62:1459-63; Smalley SV et al. Genet Mol Biol, 2015 Mar;38:30-6; Huidekoper HH et al. Eur J Pediatr, 2016 Jan;175:143-6; Stelten BML et al. J Inherit Metab Dis, 2018 Jul;41:641-646; Contreras JP et al. Rev Med Chil, 2019 May;147:658-662; Atallah I et al. Mol Genet Metab Rep, 2021 Mar;26:100719; Guenzel AJ et al. JIMD Rep, 2021 May;59:3-9; Guay SP et al. JCEM Case Rep, 2024 Feb;2:luae004). In an assay testing CYP27A1 function, this variant showed a functionally abnormal result (Cali JJ et al. J Biol Chem, 1991 Apr;266:7779-83). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

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	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.98
MPC		0.84
ClinPred		0.60	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908096; hg19: chr2-219678909;