chr2-218809700-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000784.4(CYP27A1):c.379C>T(p.Arg127Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,126 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 (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
CYP27A1
NM_000784.4 missense
NM_000784.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 0.463
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.913
PP5
Variant 2-218809700-C-T is Pathogenic according to our data. Variant chr2-218809700-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218809700-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152134Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251374Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135848
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727236
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GnomAD4 genome AF: 0.0000985 AC: 15AN: 152252Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74458
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cholestanol storage disease Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 17, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2024 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 21, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the CYP27A1 protein (p.Arg127Trp). This variant is present in population databases (rs201114717, gnomAD 0.02%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 10430841, 10775536, 17319284, 23659550, 27455001, 28623566). 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.Arg94Trp. ClinVar contains an entry for this variant (Variation ID: 65865). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27A1 protein function. This variant disrupts the p.Arg127 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8730343, 10775536; Invitae). 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. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 09, 2023 | PM2_moderate, PM3_very_strong, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 16, 2024 | In vitro functional studies suggest disrupted protein expression and heme binding (PMID: 11737215, 17697869); 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: 21604088, 31796091, 30778698, 17697869, 24836315, 11181744, 16816916, 27455001, 10430841, 28937538, 28623566, 26643207, 26550830, 31980526, 33414089, 32344004, 32531740, 23659550, 34426522, 31589614, 36380532, 37263730, 11737215, 34689324, 32714376) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 27, 2020 | ACMG classification criteria: PS4, PM2, PM3 - |
CYP27A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 28, 2022 | The CYP27A1 c.379C>T variant is predicted to result in the amino acid substitution p.Arg127Trp. This variant is alternatively referred to as p.Arg94Trp in the literature. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with cerebrotendinous xanthomatosis (Verrips et al. 1999. PubMed ID: 10430841, Table 2; Kapás et al. 2014. PubMed ID: 23659550; Zhang et al. 2016. PubMed ID: 27455001; Chen et al. 2017. PubMed ID: 28623566, Table 3; Gong et al. 2017. PubMed ID: 28937538, Table 2; Elert-Dobkowska et al. 2019. PubMed ID: 30778698, Tables 1 and 2; Jiang et al. 2020. PubMed ID: 32714376). In some of these individuals, the disorder was reported to manifest as neonatal cholestasis (Gong et al. 2017. PubMed ID: 28937538, Table 2). Functional studies suggest this variant may impact heme activity (Gupta et al. 2007. PubMed ID: 17697869, data not shown). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219674423-C-T). In ClinVar, this variant is interpreted as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/65865/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at