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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.

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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.

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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

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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.

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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

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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).

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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.

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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.

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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.

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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.

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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

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(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.

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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.

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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.

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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.

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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.

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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

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◼ 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

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PowerPoint slides of the presentation can be used for non-commercial purposes – please credit us For questions or concerns, please contact support@pharmvar.org

Thank you!

Please feel free to use any slides, but don’t forget to credit PharmVar.org

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