rs121908097

Positions:

chr2-218814702-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000784.4(CYP27A1):c.1421G>A(p.Arg474Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,038 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R474W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.88

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 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218814701-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 2-218814702-G-A is Pathogenic according to our data. 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. Variant chr2-218814702-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.1421G>A	p.Arg474Gln	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.1421G>A	p.Arg474Gln	missense_variant	8/9	1	NM_000784.4	ENSP00000258415	P1
CYP27A1	ENST00000494263.5 linkuse as main transcript	n.2133G>A		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250508

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1994	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2024	Variant summary: CYP27A1 c.1421G>A (p.Arg474Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250508 control chromosomes (gnomAD). c.1421G>A has been reported in the literature in multiple individuals affected with Cerebrotendinous Xanthomatosis (Kim_1994, Badura-Stronka_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in reducing enzyme activity in fibroblasts (Kim_1994). ClinVar contains an entry for this variant (Variation ID: 4258). The following publications have been ascertained in the context of this evaluation (PMID: 34689324, 7915755). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 474 of the CYP27A1 protein (p.Arg474Gln). This variant is present in population databases (rs121908097, gnomAD 0.006%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 7915755, 28894950, 29434128). This variant is also known as 441 [CGG (Arg) to CAG (Gln)] and Arg441->Gln. ClinVar contains an entry for this variant (Variation ID: 4258). 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%. This variant disrupts the p.Arg474 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7915755, 10406988, 12270007, 17319284). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2023	Functional studies showed undetectable enzyme activity in the skin fibroblasts of patients homozygous for the R474Q variant (PMID: 7915755); 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: 16816916, 29434128, 32344004, 30891321, 28894950, 25447658, 7915755, 31589614, 34493867, 2072121, 36312475, 37970240, 33967188, 33977023, 9186905, 20558929, 34479889, 33414089) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

CYP27A1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2023

The CYP27A1 c.1421G>A variant is predicted to result in the amino acid substitution p.Arg474Gln. This variant, also described as Arg441->Gln, has been reported in the homozygous, compound heterozygous and heterozygous states in multiple unrelated individuals with cerebrotendinous xanthomatosis (Table 1, Kim KS et al 1994. PubMed ID: 7915755; Table 1, Stelten BML et al 2017. PubMed ID: 28894950; Sasamura A et al 2018. PubMed ID: 29434128; Miyamoto M et al 2019. PubMed ID: 30891321). A study of skin fibroblasts derived from an individual homozygous for this variant showed reduced sterol 27-hydroxylase activity (>98%) compared to control (Table 1, Kim KS et al 1994. PubMed ID: 7915755). Other missense variants at this residue (p.Arg474) have been reported in individuals with cerebrotendinous xanthomatosis suggesting that this amino acid position is critical to enzyme function (Table 1, Kim KS et al 1994. PubMed ID: 7915755; Nozue T et al 2010. PubMed ID: 20558929). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219679425-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.98

Loss of methylation at R474 (P = 0.0277);

MVP

0.95

MPC

0.77

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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