2-218782184-T-C

Variant summary

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

The NM_000784.4(CYP27A1):ā€‹c.2T>Cā€‹(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: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000082 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 start_lost

Scores

3
6
7

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]

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
CYP27A1NM_000784.4 linkuse as main transcriptc.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 UniProt
CYP27A1ENST00000258415.9 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/91 NM_000784.4 ENSP00000258415 P1
CYP27A1ENST00000466602.1 linkuse as main transcriptn.11T>C non_coding_transcript_exon_variant 1/32
CYP27A1ENST00000494263.5 linkuse as main transcriptn.436T>C non_coding_transcript_exon_variant 1/72
CYP27A1ENST00000445971.1 linkuse as main transcriptc.2T>C p.Met1? start_lost, NMD_transcript_variant 1/55 ENSP00000404945

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152106
Hom.:
0
Cov.:
32
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:
28
AN:
133178
Hom.:
0
AF XY:
0.000344
AC XY:
25
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.:
0
Cov.:
31
AF XY:
0.000127
AC XY:
87
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:
4
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
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:
11

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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 01, 2022This 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 submitterclinical testingRevvity Omics, RevvityMay 04, 2020- -
CYP27A1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 23, 2023The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 21, 2021Variant 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 submitterclinical testingEurofins Ntd Llc (ga)May 04, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
23
DANN
Benign
0.87
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.0075
Eigen_PC
Benign
-0.033
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Benign
-0.65
T
MutationTaster
Benign
1.0
D
PROVEAN
Benign
-1.1
N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0080
D
Polyphen
0.81
P
Vest4
0.50
MutPred
0.94
Gain of helix (P = 0.062);
MVP
0.87
ClinPred
0.11
T
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.

Other links and lift over

dbSNP: rs759003992; hg19: chr2-219646907; API