2-218812266-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000784.4(CYP27A1):c.491G>C(p.Arg164Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 6.75

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218812265-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 593797.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.491G>C	p.Arg164Pro	missense_variant	3/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.491G>C	p.Arg164Pro	missense_variant	3/9	1	NM_000784.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152212

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:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251450

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00000455

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	Reported as a heterozygous variant in a patient with an inborn error of bile acid metabolism in the published literature; however, a second variant in CYP27A1 was not reported (Chen et al., 2019); 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: 30366773) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2023	- -

Cholestanol storage disease

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

CYP27A1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2023

The CYP27A1 c.491G>C variant is predicted to result in the amino acid substitution p.Arg164Pro. This variant has been reported in a patient with an inborn error of bile acid metabolism; however, this patient lacked a second variant in CYP27A1 and also had a homozygous variant in the AKR1D1 gene and a heterozygous variant in the ABCC3 gene (Patient 04 in Table 4, Chen et al 2018. PubMed ID: 30366773). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219676989-G-C), which may be too common for a pathogenic variant. This variant has conflicting interpretations in ClinVar regarding its pathogenicity ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/498357). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.491G>C (p.R164P) alteration is located in exon 3 (coding exon 3) of the CYP27A1 gene. This alteration results from a G to C substitution at nucleotide position 491, causing the arginine (R) at amino acid position 164 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.050

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;T

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.62

Gain of catalytic residue at N162 (P = 0.0287);.;

MVP

0.78

MPC

0.86

ClinPred

0.91

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.93

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