1
CYP Nomenclature - 1996
Estabrook
In order to provide the science field a
with a unified nomenclature, the star
(*) allele nomenclature has been
devised to “encourage scientists
worldwide to speak the same
language” and to avoid home-made
allele designations that can confuse
the scientific literature.
Johnson
Waterman
Guengerich
A group of experts came together in the mid 1990s to devise the first pharmacogene
nomenclature to “encourage scientists worldwide to speak the same language”. The
new Star (*) nomenclature was first applied to CYP2D6, a major drug metabolizing
enzyme, for which there was a growing number of allelic variants. The star (*)
nomenclature was expanded in 2000 to include all other polymorphic CYP genes.
Human P450 Gene Nomenclature - 2000
The star (*) nomenclature was expanded in 2000 to include other polymorphic CYP
genes
www.cypalleles.ki.se/ - 2002
Magnus Ingelman-Sundberg
Karolinska Institute, Stockholm, Sweden
The number of allelic variants was growing fast – too many to keep updates in
paper format. The Human CYP P450 Allele Nomenclature Database was launched
in 2002 under the direction of Magnus Ingelman-Sundberg at the Karolinska
Institutet in Stockholm, Sweden.
www.cypalleles.ki.se/
Don’t forget to update
your bookmark from
www.cypalleles.ki.se/
to
https://www.pharmvar.org/
After dedicating many years of his distinguished career to developing and
maintaining the CYP Allele Nomenclature resource together with Sarah Sim who
served as the Webmaster for twelve years, both Magnus Ingelman-Sundberg and
Sarah Sim have retired from the nomenclature site to focus on other projects.
Once again, a group of experts came together and mutually agreed that the
Nomenclature database is an invaluable resource to the entire field of PGx
(research, clinical, commercial) and must not disappear. Andrea Gaedigk (Children’s
Mercy Kansas City) and Teri Klein (PharmGKB) devised a plan that came to fruition
by founding the PharmVar Consortium.
The Nomenclature site has transitioned to PharmVar on September 26 of 2017.
Update your bookmark to https://www.pharmvar.org/ for direct access.
Tables rely
on allele
definitions
CPIC guideline for tamoxifen
CPIC guidelines provide recommendations based on diplotypes for several drug
metabolism genes including CYP2C9, CYP2C19 and CYP2D6 as shown for the
CYP2D6/tamoxifen guideline. Allele definitions are based on those provided by
PharmVar.
6
PharmGKB tables use star alleles
◼ Published literature typically refers to star alleles rather
individual variants for CYPs and some other PGx genes
◼ PharmGKB reference tables use star alleles for CYP
genes: allele frequency and function, diplotype-
phenotype mapping
◼ Utility of PharmGKB reference tables
Support basic and medical research
PharmGKB literature annotations
PharmGKB submissions to ClinVar that require allele
definitions
CPIC guideline evidence review and prescribing
recommendations
PharmCAT
Star allele designations are widely used.
7
Tools call star alleles from NGS data
Astrolabe
http://www.childrensmercy.org/Health_Care_Professionals/Research/Pediatric_Genomic_Medicine/Software_Tools/ www.pharmgkb.org/page/pharmcat
Other tools include Stargazer and Aldy
Bioinformatic tools such as Astrolabe (developed at CMH), Stargazer, Aldy, Cyrius
and StellarPGx utilize PharmVar allele/haplotype definitions. PharmCAT, another
bioinformatic tool provides a pipeline to call a person’s genotype and produce
recommendations using CPIC guidelines
8
Clinical Test Reports also Use Star Nomenclature
Unified nomenclature facilitates
standardized test reporting
As highlighted in yellow, the star (*) nomenclature is almost exclusively used to
display patients’ genotypes on clinical PGx test reports obtained to guide
therapeutic decision making.
9
Research labs
Clinical labs
Commercial labssubmit
utilize
PharmGKBOther consortia/ databases
PharmVar.orgHouses Allelic Variation
Scientific Advisory Board
Steering Committee
oversight
advise
feedback/input review/designate novel variants
PharmVarConsortium members
PharmVarExpert Panels
Overview of the PharmVar Consortium. Community input and active participation
is key. PGx experts are encouraged to become a member and volunteer to
participate (e.g. serving as a gene expert). PharmVar currently has over 150
members. Efforts are coordinated between PharmVar and the PharmGKB with the
goal to utilize standardized PGx nomenclature throughout all PGx efforts.
Gene Expert Panels
◼ Each panel consist of a chair and co-chair, gene
experts and PharmGKB representatives
◼ Experts have research, clinical and/or industry backgrounds
– ideally all are represented in a panel
◼ International representation
◼ Curate information as a gene is transferred into the PharmVar database
◼ Instrumental role in building nomenclature for PharmVar genes for
which no formal nomenclature exists. This includes the development of
documents, contribute to progress reports or GeneFocus reviews
◼ Review submissions and recommend allele designation(s)
Overview of what gene experts do
11
Notable database features include:
• All variants are consistently mapped to current genomic and transcript reference sequences
(RefSeqs) and the GRCh37 and GRCh38 genome builds
• The variation window offers display of variants in different formats: HGVS and PharmVar style
• Different count modes (count from sequence start or the ‘A’ of the ATG start codon)
• Gene pages have customizable display features making it easy to find information
• The PharmVar star allele naming system supports cataloging of suballeles
• Core allele definitions collapse all suballeles into a single reportable definition
• Comparative Allele ViewEr (CAVE) allows graphical comparison of core alleles
• Each haplotype has a unique PharmVar ID number
• Haplotype evidence levels indicate how strong the information is for a haplotype definition
• Download options in different formats
• API services
The PharmVar database has many more features compared to the original
Nomenclature website. Standardized allele definitions using RefSeqs or LRGs
(Locus Reference Genomic records) facilitate standardized and uniform reporting of
variants across fields. Gene pages are designed to provide information in user-
friendly and intuitive ways. PharmVar improved cataloguing by introducing a revised
haplotype naming system, as well as unique PharmVar ID numbers to track each
haplotype (see Gaedigk et al. CPT Jan;105(1):29-32).
12
HOME
Link to archive
From the PharmVar landing page gene information can be accessed through the
GENES tab in the menu bar. The content of the Legacy Nomenclature site
(cypalleles.ki.se) as of Sept 26, 2017, is available through the ARCHIVE link.
13
ABOUT
Please use any of the slides of this presentation
As long as you give us credit
Find important information about the PharmVar Consortium under the ABOUT tab in
the menu bar including of how to cite PharmVar. All slides of this presentation can
be freely used as long as you give us credit.
14
SUBMISSIONS
The form for new haplotype submissions can be found under the SUBMISSIONS
tab of the menu bar. The allele definition and evidence level criteria document
can be accessed through the SUBMISSIONS dropdown menu.
15
PharmVar uses a number of conventions for storing and displaying allelic data consistently.
As summarized in the STANDARDS document (accessible through the GENE tab),
PharmVar relies on public standards and data sources wherever possible. Note that this may
cause some variant positions (especially indel variants and variants in repeat or
homopolymer sequences) to display differently among databases.
STANDARDS
STANDARDS document describes how data are displayed
The same standards are being applied to all genes in the PharmVar database as
detailed in the STANDARDS document. Please familiarize yourself with these
standards before using the database.
16
Create custom views with the Haplotype
Filter and Column Selector tools
Important gene documents: Read Me, Change log and structural information
CAVE tool
Variants for CYP2D6 are mapped to
gene and transcript RefSeqs,
GRCh37 and 38, as well as a legacy
sequence(M33388) – click to change
view
Database Overview – The Gene Page
Gene name(s), links to external
resources, download gene information
select count mode
Haplotype evidence levels
Core allele definition CPIC clinical allele function
PharmVar provides a set of accompanying documents to guide the user. Each gene
page has a READ ME document summarizing important gene and reference
sequence information along examples/use cases. The CHANGE LOG document
keeps track of all major changes (transition to PharmVar, corrections, revisions, new
(sub)allele definitions added, etc.). Genes with structural variants such as CYP2D6
shown here also have a STRUCTURAL VARIATION document providing a
summary of gene deletions, duplications, and hybrid genes.
Coordinates are mapped to the current genomic and cDNA reference sequences
(RefSeq) as well as the GRCh37 and 38 genome builds (select the sequence of
interest by clicking on it). For CYP2D6, coordinates are also shown for M33388, a
sequence that has been used in the past (PharmVar encourages the use of RefSeq
coordinates optimally cross-referenced with M33388). The user can toggle
between different number systems - coordinates can be visualized counting from
the start of a sequence or counting from the ATG start codon.
In the current view SNVs highlighted in blue have a rs number. Clicking on any
SNP will activate the slide-in Variant Positions Window (details see next slide).
Impact of a SNV is no longer shown in a separate column, but is displayed in
brackets after the causative SNV. A column has been added for the revised
haplotype naming system (cross-referenced to legacy names), PharmVar IDs
17
(each haplotype’s unique ID number) and evidence levels. Users can now also
customize page views using the Haplotype Filters and Column Selection tools.
In collaboration with the PharmGKB, PharmVar is introducing core allele definitions
(see STANDARDS and READ ME documents for details). Core alleles are
highlighted by gray background and core SNVs are flagged with the PharmVar logo.
Since function is believed to be the same for all alleles with the same star number,
function is now displayed in the core allele line.
The Comparative Allele ViewEr (CAVE) tool allows graphical comparisons of core
alleles. The user can access the CAVE tool via the Graphical View button. Please
consult the READ ME document for more information and examples before
using CAVE.
17
SNV annotations per HGVS
Database Overview – The Variation Window
Frequency of SNV
Link out to dbSNP
Filter to view all variants with this SNV
Variation
window
slides in
upon
clicking on
a SNV
PharmVar style SNV
annotations
The Variation Window (activated by clicking on a SNV on the gene page)
shows positions of a SNV using different conventions. The middle section displays
SNV positions on the gene and transcript reference sequences counting from their
respective start sites and the A of the ATG start codon, as well as GRCh 37,
GRCH38 and the M33388 legacy sequence. Annotations for the per HGVS is
provided in the top section (note that positions for indels may not always correspond
between the two annotation systems due to right vs left aligning).
From here the user can link-out to dbSNP, display only those haplotypes with the
selected SNP by using the “Show Haploypes With This Variant” filter option, and
see the frequency of the SNV (as provided by GnomAD and the 1000 Genomes
Project). Please note that the frequency does not necessarily represent the
frequency of the haplotype of the allele.
18
Comparative Allele ViewEr (CAVE)
Select allelic variants for comparison from the selection pad and click the
‘Compare Haplotypes’ button. The CAVE tool displays which core SNVs are shared
among alleles. Note that a core SNV of a particular haplotype may not be part of the
core definition of another but may be found on one or more suballeles. More
detailed information and examples are provided in the READ ME documents
of the genes that have the CAVE feature. We strongly encourage all users to
consult these documents before using CAVE.
19
NUDT15First non-CYP pharmacogene in PharmVar
◼ NUDT15 genetic information is included in the 2018 update of the CPIC guideline on
thiopurine dosing recommendations
◼ No centralized resource existed for NUDT15 to keep track of allelic variation
◼ Expert panel First convened in April 2018
Reviewed known/published allelic variants
Assessed whether existing *names conform with PharmVar rules for
haplotype designation
Contacted authors to submit their [published] haplotypes to PharmVar
Reviewed and assigned star names
Panel reviewed two submissions
◼ NUDT15 nomenclature published Yang et al, CPT 105:1091-1094, 2019, PMID 30515762)
PharmVar expanded its repertoire by adding its first non-CYP gene. The slide
provides a brief overview of the process of establishing formal nomenclature of
NUDT15. Several novel variants were discovered and submitted during the process.
20
DPYD – new page format
◼ Although star nomenclature was utilized
along trivial names or rs numbers, no
centralized resource existed for DPYD to
keep track and curate information
◼ Star nomenclature based on haplotypes was
deemed impractical for DPYD due to the size
of the gene (843,317 bp) making haplotype
phasing across all exonic regions difficult
◼ Most consequential sequence variants are
rare or extremely rare
◼ To address these gene-specific challenges in
nomenclature, PharmVar developed a gene
page format using rs IDs as PharmVar
names instead of star allele designations
◼ rs numbers serve as variant names
◼ SNVs can be sorted by frequency
Sort variants by frequency
PharmVar expanded its repertoire by adding another non-CYP gene. A second
page format was developed to accommodate this gene for which haplotype-based
nomenclature was deemed impractical by the gene experts. Unique to this page
format is that variants can be sorted by their frequency.
21
PharmVar GeneFocus Reviews
◼ PharmVar has launched a series of GeneFocus reviews published in CPT
◼ Each GeneFocus provides a comprehensive overview of the gene, describes genetic
variation and PharmVar efforts
PharmVar GeneFocus in preparation
CYP3A5
CYP2D6 copy number variation
All PharmVar publications can be found under
the RESOURCE tab
Please cite us
PharmVar launched a series a GeneFocus review articles providing an overview of
the gene, explains why standardized nomenclature is needed and details PharmVar
efforts. Please cite us as you publish your own work. All PharmVar publications are
freely available through the RESOURCES tab
22
◼ Still transitioning other CYP genes into the PharmVar database
◼ The first drug transporter, SLCO1B1, is coming soon!
◼ More content and functional features down the road Convert accompanying information files to HTML
Cross-referencing Coriell reference materials with haplotype
Online submission portal
Biochemical and in-silico function information
Others (suggestions are welcome)
In the works…..
The home for PGx Variation
The PharmVar team and PharmGKB collaborators are keeping busy. We continue
to work on additional cool features. We welcome feedback and suggestions for
features
23
PowerPoint slides of the presentation can be used for non-commercial purposes – please credit us For questions or concerns, please contact [email protected]
Thank you!
Please feel free to use any slides, but don’t forget to credit PharmVar.org
24