rs121908098

Positions:

chr2-218814701-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000258415.9(CYP27A1):c.1420C>T(p.Arg474Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R474Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CYP27A1
ENST00000258415.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.04

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 18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000258415.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218814702-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 2-218814701-C-T is Pathogenic according to our data. Variant chr2-218814701-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218814701-C-T is described in Lovd as [Pathogenic]. Variant chr2-218814701-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.1420C>T	p.Arg474Trp	missense_variant	8/9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.1420C>T	p.Arg474Trp	missense_variant	8/9	1	NM_000784.4	ENSP00000258415	P1
CYP27A1	ENST00000494263.5 linkuse as main transcript	n.2132C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250398

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:12

Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2020	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2,PM3_Strong,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 16, 2021	This variant was previously reported in compound heterozygous state in an chinese individual affected with peripheral neuropathy [PMID: 33313117]. It was reported as fourth most common variant in cerebrotendinous xanthomatosis Japanese patients and was previously identified in 61-year-old Japanese patient with pure spinal form of cerebrotendinous xanthomatosis, who developed dysesthesia of the lower limbs and gait disturbance at 57 years of age [PMID: 32581172]. The p.Arg474Trp variant was previously classified as ‘deleterious’ based on insilico predictions [PMID: 32344004]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 474 of the CYP27A1 protein (p.Arg474Trp). This variant is present in population databases (rs121908098, gnomAD 0.02%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 7915755, 10406988, 12270007, 17319284, 22336472, 29321515). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg441Trp. ClinVar contains an entry for this variant (Variation ID: 4259). 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 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: 12270007). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 12, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2023	- -
Pathogenic, no assertion criteria provided	research	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	Feb 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Oct 11, 2024	A heterozygous missense variation in exon 8 of the CYP27A1 gene that results in the amino acid substitution of tryptophan for Arginine at codon 474 was detected. The observed variant c.1420C>T (p.Arg474Trp) has a minor allele frequency of 0.0012% and 0.0017% gnomAD and ExAC databases. The in silico prediction of the variant is damaging by Revel, MutationTaster2, MetaLR, BayesDel and DANN. In summary, the variant meets our criteria to be classified as a variant of pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1994	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 22, 2017	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2023

Published functional studies demonstrate a damaging effect on enzyme activity (Gupta RP et al., 2007; Kim KS et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8614539, 34426522, 33414089, 7915755, 32868181, 33494148, 17697869, 33763395, 32581172, 35614401, 28937538) -

CYP27A1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

The CYP27A1 c.1420C>T variant is predicted to result in the amino acid substitution p.Arg474Trp. This variant, sometimes described as R441W using legacy nomenclature, has been reported in homozygous and compound heterozygous individuals with cerebrotendinous xanthomatosis (Kim et al. 1994. PubMed ID: 7915755; Rystedt et al. 2002. PubMed ID: 12270007; Wang et al. 2007. PubMed ID: 17319284; Gong et al. 2017. PubMed ID: 28937538). Experimental studies in vitro indicate that the p.Arg474Trp variant has less than 5% of the enzyme activity compared to wild-type enzyme (Rystedt et al. 2002. PubMed ID: 12270007). An alternate missense change at the same amino acid position, p.Arg474Gln, has also been reported in patients with cerebrotendinous xanthomatosis (Kim et al. 1994. PubMed ID: 7915755; Gong et al. 2017. PubMed ID: 28937538). The c.1420C>T (p.Arg474Trp) variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD. Based on the available evidence, we classify this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.97

Loss of methylation at R474 (P = 0.0277);

MVP

0.97

MPC

0.73

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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