chr2-218782184-T-C

Position:

chr2-218782184-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000784.4(CYP27A1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,536,316 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 3.08

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 11 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-218782184-T-C is Pathogenic according to our data. Variant chr2-218782184-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282570.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/9	1	NM_000784.4	ENSP00000258415	P1
CYP27A1	ENST00000466602.1 linkuse as main transcript	n.11T>C		non_coding_transcript_exon_variant	1/3	2
CYP27A1	ENST00000494263.5 linkuse as main transcript	n.436T>C		non_coding_transcript_exon_variant	1/7	2
CYP27A1	ENST00000445971.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/5	5		ENSP00000404945

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152106

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:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000210

AC:

AN:

133178

Hom.:

AF XY:

0.000344

AC XY:

AN XY:

72660

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000816

AC:

113

AN:

1384210

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

683160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00137

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.28e-7

Gnomad4 OTH exome

AF:

0.0000694

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74318

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:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.000211

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 01, 2022	This sequence change affects the initiator methionine of the CYP27A1 mRNA. The next in-frame methionine is located at codon 95. This variant is present in population databases (rs759003992, gnomAD 0.1%). Disruption of the initiator codon has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 24174808, 33830582). ClinVar contains an entry for this variant (Variation ID: 282570). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 04, 2020	- -

CYP27A1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2023

The CYP27A1 c.2T>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in an individual with cerebrotendinous xanthomatosis (Bajaj et al 2013. PubMed ID: 24174808). This variant has also been reported in the compound heterozygous state in a family diagnosed with cerebrotendinous xanthomatosis in three affected individuals and one clinically unaffected individual assessed at 46 years of age (Table 1, Stelten et al 2021. PubMed ID: 33830582). This variant is reported in 0.12% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org). However, other protein-truncating variants near the start site of this gene have been reported as causative (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). Therefore, this variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 21, 2021

Variant summary: CYP27A1 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (p.Met95). Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 133178 control chromosomes, predominantly at a frequency of 0.0012 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2T>C has been reported in the literature in individuals affected with Cerebrotendinous Xanthomatosis (Bajaj_2013, Stelten_2021). However, one family study showed that this variant may not co-segregate with the disease (Stelten_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.21

Eigen

Benign

-0.0075

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.65

MutationTaster

Benign

1.0

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.81

Vest4

0.50

MutPred

0.94

Gain of helix (P = 0.062);

MVP

0.87

ClinPred

0.11

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.69

gMVP

0.75

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