NAT2 now released on PharmVar

PharmVar and PharmGKB are excited to share that NAT2 has been transitioned into the PharmVar database and updated accordingly on PharmGKB. NAT2 metabolizes several pharmaceutical substrates, including isoniazid, hydralazine, amifampridine, procainamide and sulfonamides, as well as some highly carcinogenic arylamines. NAT2 enzymatic activity varies considerably between individuals, due to polymorphisms in NAT2 coding sequence that may be found more commonly in some populations than others. NAT2 alleles usually contain more than one single nucleotide variation (SNV), with specific variants defining different allelic groups. Given the complex haplotypic nature of NAT2 alleles, phasing of SNVs to determine diplotype from genotype can be difficult. It is therefore important to maintain up-to-date information regarding sequence variation and star allele (haplotype) definitions to facilitate accurate genetic testing, genotype interpretation and phenotype prediction in the research and clinical settings.

Some drastic changes have been made to NAT2 nomenclature during transition from the original Database of Arylamine N-Acetyltransferases (NATs) to the new “star” allele definitions on PharmVar:

The NAT2 reference allele has now changed: The NG_012246.1 RefSeq differs from X14672.1 (which was used in the past to define star alleles) at the position that corresponds to c.803 (rs1208), where X14672.1 has “A” while NG_012246.1 has “G”. Thus, depending on which reference sequence is utilized, this position is reported as either reference or variant. The transition of allele definitions to the NG_012246.1 RefSeq caused “variant switching”, meaning that all star alleles which were previously described as having c.803A>G lost this variant, as “G” is now considered reference, while all other star alleles gained c.803G>A, as “A” is now considered variant. 

 

The new reference allele is now catalogued as NAT2*1: The sequence of NG_012246.1 RefSeq corresponds to the allele that was formerly described as NAT2*12A. Its renaming as NAT2*1.001 facilitates the application of PharmVar rules to NAT2 allelic nomenclature, while it also enables the use of NAT2*1 name to describe the reference allele, in line with the star allele nomenclature of other pharmacogenes. To avoid confusion during the transition from the legacy to the new nomenclature, *12 is now retired. Having a NAT2*1 allele grouping in place also facilitates NGS analyses using GRCh38 as a reference.

 

NAT2*4 is no longer considered as the reference allele: Alleles carrying c.803G>A as their only amino acid changing SNV will be called as *4 according to the new nomenclature. This includes the former NAT2*4 reference allele of sequence X14672.1, now considered a variant and listed as NAT2*4.001. Although this will no longer be used as a reference, it is considered to be functionally equivalent to NAT2*1.001 (formerly NAT2*12A) and may still be used to compare the enzymatic or structural properties of polymorphic NAT2 proteins. 

 

Star alleles have been renamed: Several NAT2 star alleles have been renamed to conform to PharmVar rules during the transition from the legacy nomenclature to the PharmVar database.

 

Not all previously defined star alleles have been transferred: In the past, it has not always been clear how a NAT2 haplotype was determined. Many have been inferred via computational phase analysis and were not verified experimentally. In the case of haplotypes where the available evidence from the literature was deemed insufficient to support confident allele definition, those haplotypes were not transferred to PharmVar, but they will remain posted on the original Database of Arylamine N-Acetyltransferases (NATs).

 

PharmGKB-annotated NAT2 alleles that are not transitioned into PharmVar will remain on PharmGKB with the original Database of Arylamine N-Acetyltransferases (NATs) name (e.g., NAT2*6J). PharmVar-transitioned NAT2 alleles are indicated on PharmGKB NAT2 allele pages with the new "PharmVar Allele" tag (e.g., NAT2*4).

 

The requirements for new allele definition have changed: In the past, reporting only the SNVs in the NAT2 coding region was sufficient to define new star alleles. According to PharmVar rules, new NAT2 alleles must cover SNVs within defined coordinates that enclose the 5’ untranslated region (including the untranslated first exon), the coding exon, the exon/intron junctions, and the entire 3’ untranslated region relative to genomic reference sequence NG_012246.1. Former alleles covering only the coding region have been annotated with a limited evidence level, as they may have additional variants that were not captured when the allele was first defined.

 

During the course of updating NAT2 nomenclature, we have been able to confirm several of the former haplotypes, while also identifying new ones. PharmVar encourages submissions of novel haplotypes for star allele definition, as well as for existing definitions to either raise their evidence levels from Limited or Moderate to Definitive, or to solidify their status of Definitive. 

Additional information has been summarized in the Read Me and Change Log documents available on the PharmVar NAT2 page. Also please consult the “NAT2 Look-up” table available under “More Documents” on the same page for an up-to-date record of alleles transferred and a quick reference of PharmVar and legacy star allele names. 

We would like to thank all members of the PharmVar NAT2 Gene Expert Panel for their massive contribution to this project, as well as the NAT Gene Nomenclature Committee for their services to the NAT community since 1998.

ClinPGx 2024 Registration and Abstract Submission Open

 

REGISTRATION OPEN

In collaboration with CPIC, PharmGKB, PharmCAT and PharmVar, the Penn Institute for Biomedical Informatics will be hosting the ClinPGx 2024: Knowledge, Implementation, Education meeting on June 20th and 21st, 2024 in Philadelphia, PA. This meeting will provide educational content to cover all aspects of PGx implementation, including knowledgebases, implementation strategy, informatics, use of AI in precision medicine, clinical laboratory insights, and more.

Participants are invited to submit abstracts for the poster sessions. You must be registered for the meeting before your abstract will be accepted.

Please note breakfast & lunch will be provided all conference days.

Registration and detailed agenda

REMINDERS / DEADLINES:

March 22, 2024: Deadline for Abstract Submission. Abstract submission form link here.

April 30, 2024: Deadline for $350 Registration Fee (Starting May 1st, registration fee will be $450)

May 20, 2024: Deadline for Hotel Reservations. Click HERE for hotels offering special rates.

June 1, 2024: Deadline to register for the event.

Announcement of PharmVar Content Changes

PharmVar continues to evolve and strive to offer high-quality content to our global users. To allow us to bring new clinically relevant content to PharmVar we needed to make some difficult decisions and ‘retire’ several CYP genes. This decision is based on a newly developed points-based rating system (0-100 points) that allows us to prioritize which genes to maintain and which genes to evaluate for future introduction into PharmVar. More detailed information regarding PharmVar gene content and prioritization will be posted under the GENES tab once these changes have taken effect May 12, 2023.

The following genes were not considered pharmacogenes by PharmVar due to their contribution to lipid and steroid metabolism and/or associations with disease and will be retired:  CYP4A11, CYP4A22, CYP4B1, CYP17A1, CYP19A1, CYP21A2, CYP26A1, TBXAS1  and PTGIS (0 points each), though several of these genes have variant and low level clinical annotations on PharmGKB. Other databases such as ClinGen and/or ClinVar may also be consulted for variation annotations. These genes were listed by PharmVar as ‘legacy’ genes. POR (3 points) was also listed as a legacy gene.  The following genes were transitioned into the PharmVar database, but never curated by an expert panel nor any additional data added: CYPs  1A1, 1B1, 2E1, 2F4, 2J2, 2R1, 2S1, 2W1, 3A7 and 3A43. These genes were not deemed to be clinically important pharmacogenes by the PharmVar Steering Committee based on having 0 points in the ranking system and will also be retired. Furthermore, the link to the archived Human Cytochrome P450 (CYP) Allele Nomenclature database record (last version by cypalleles.ki.se in 2017) will be deactivated to discourage use of outdated information (a copy can be requested through support@pharmvar.org).

If new data emerges and rankings change, a gene may be reintroduced to PharmVar. 

 

NAT2 is currently undergoing curation and is anticipated to be transferred from the Databases of Arylamine N-acetyltransferases (NATs) to PharmVar in summer 2023. The introduction of NAT2 into the PharmVar database is timely as CPIC is initiating a guideline for the NAT2/hydralazine gene-drug pair.  Additionally, NAT2 has multiple clinical annotations and mulitple annotated FDA and other regulatory agency labels.

 

As always, PharmVar values your feedback and suggestions support@pharmvar.org.

CYP2D6 allele function update

The CYP2D6 allele functionality file has been re-evaluated and updated by experts involved in CYP2D6-related CPIC guidelines. CYP2D6 functions are now assigned up to star allele 163. 

Part of the re-evaluation focused on alleles that include 100C>T (P34S) (*10 key SNP). Furthermore, the activity value of several decreased function alleles, e.g. *9 and *41, was downgraded to 0.25. 

The updated file can be accessed through CYP2D6-related guidelines on the CPIC website and through the CYP2D6 resource page on PharmGKB. The updated functions are also displayed on the PharmVar CYP2D6 page .

PharmVar updates for CYP3A4 star allele definitions

 PharmVar announces several updates for CYP3A4 star allele definitions.

Retirement of the CYP3A4*1G allele: this allele was defined by a common variant in intron 10 (c.1026+12G>A) which was also found on many other haplotypes (or star alleles). PharmVar transiently designated the CYP3A4*1G allele as *36 due to a possible role of c.1025+12G>A being involved in the regulation of CYP3A4 expression. However, owing to the growing body of inconsistent findings regarding associations of c.1026+12G>A and higher or lower expression levels and/or CYP3A4 activity, PharmVar withdrew this redesignation in January 2023 (v5.2.17) which led to the retirement of the CYP3A4*36 (former *1G) allele. Per PharmVar rules, intronic variants are only utilized for star allele definitions if there is convincing evidence that the variant impacts protein function. Therefore, c.1026+12G>A was also removed from all other star allele definitions.

CYP3A4 gene regulation is complex and appears to be governed by a layer of processes, among them long noncoding RNAs, microRNAs and transcription factors which may also influence CYP3A5 activity. Furthermore, there is substrate overlap between CYP3A4 and CYP3A5 and thus, variation in the CYP3A5 gene, further complicates the characterization of CYP3A4 allele function. Investigators are encouraged to include c.1026+12G>A in their carefully designed investigations to produce conclusive evidence regarding the functional impact of c.1026+12G>A.      

We would also like to highlight the addition of a novel star allele, CYP3A4*38 which is characterized by two variants which on their own define CYP3A4*3 and *11. Noteworthy, the CYP3A4*3-defining variant c.1334T>C (p.M445T) has also been found together with the intronic SNP defining CYP3A4*22; this allele was designated CYP3A4*37. Consequently, samples heterozygous for these SNPs could have CYP3A4*1/*37 or *3/*22 or *1/*38 or *3/*11 genotypes, respectively. Since the functional impact of c.1334T>C (p.M445T) remains elusive it is unknown whether alternate genotypes differ in function.

Lastly, the evidence level of several alleles has been updated from ‘Limited’ or ‘Moderate’ to ‘Definitive’ indicating that these alleles are now fully characterized. 

These efforts were only possible by the dedicated work of the PharmVar Team and the CYP3A4 gene experts for volunteering their time and expertise.

CYP4F2 is now fully curated by PharmVar

CYP4F2 contributes to the synthesis of cholesterol, steroids and other lipids. It has been shown to regulate the bioavailability of vitamin E and vitamin K, a co-factor that is critical to blood clotting. Variations in this important pharmacogene can affect vitamin K levels and thus, the dosing of vitamin K antagonists such as the widely used anticoagulant drug warfarin (CPIC level A and PharmGKB 1A evidence level) among others.

We are excited to announce that CYP4F2 is now fully curated by PharmVar and its gene page content reviewed by an international expert panel. Furthermore, the PharmVar Team has generated new data to provide a more comprehensive catalog of genetic variation of this gene. Not only have the two previously defined CYP4F2*2 and *3 now been fully characterized, several other novel haplotypes (or star alleles) have been identified and designated by PharmVar. Notably, the new and relatively commonly observed CYP4F2*4 allele has both sequence variants that otherwise define *2 (c.34T>G, W12G) and *3(c.1297G>A, V433M), respectively while the other three novel star alleles (CYP4F2*5, *6 and *7) are each characterized by a single amino acid change. Interestingly, CYP4F2*5 and *6 appear to be absent or rare in Asian populations; in contrast, *7 seems to be mostly present in African populations and their descendants. These new star alleles may contribute to unexplained variability in daily warfarin dosage requirements in non-White populations. We encourage the research and clinical communities to include this new knowledge in their investigations.

PharmVar GeneFocus paper for SLCO1B1 is published

The PharmVar GeneFocus: SLCO1B1 paper has just been published by Clinical Pharmacology & Therapeutics.

 

This review provides a general overview of SLCO1B1 as well as a deeper dive into its nomenclature. This GeneFocus covers genetic variability, functional impact, clinical relevance, gene nomenclature before and after PharmVar updates, methods for allele characterization and how the new nomenclature impacts pharmacogenetic testing and interpretation. Specific details of changes to allele definitions can be found on the PharmVar SLCO1B1 page and on the Change Log tab of the SLCO1B1 Allele Definition Table available from PharmGKB. This new nomenclature has been used in the recently published CPIC guideline on statin-associated musculoskeletal symptoms.

 

For more details, please see:

PharmVar GeneFocus: SLCO1B1

Clin Pharmacol Ther. 2022 Jul 7. doi: 10.1002/cpt.2705. 

Laura B. Ramsey, Li Gong, Seung-been Lee, Jonathan B. Wagner, Xujia Zhou, Katrin Sangkuhl, Solomon M. Adams, Robert J. Straka, Philip E. Empey, Erin C. Boone, Teri E. Klein, Mikko Niemi, Andrea Gaedigk.

PMID: 35797228

CYP2A6 now released on PharmVar

PharmVar and PharmGKB are excited to share that CYP2A6 has been transitioned into the PharmVar database. CYP2A6 metabolizes several substates including coumarin, nicotine, aflatoxin B1, nitrosamines, and some pharmaceuticals. Owing to its highly polymorphic nature, CYP2A6 activity varies considerably between individuals. Due to the complex nature of the CYP2A gene locus that contains not only CYP2A6, but also the highly similar CYP2A7 and CYP2A13 genes, CYP2A6 genotype analysis and characterization of allelic variants is not trivial. It is therefore of utmost importance to have up-to-date information regarding sequence variation and star allele (haplotype) definitions to facilitate accurate genetic testing, data interpretation and phenotype prediction in the research and clinical settings.  

The PharmVar CYP2A6 gene experts have systematically reviewed and curated all star allele definitions that were previously issued by the CYP450 Nomenclature databases (these were last updated in 2014 and can be accessed through the archive). Some notable changes include:

• Variants and star alleles are now defined using the most current genomic reference sequence
• Several alleles have been merged, revised and/or redesignated (legacy allele designations are cross-referenced)
• Regions used for allele definitions have been updated
• Structural variants including a common conversion at the 3’UTR have been updated to current knowledge and are detailed in the ‘Structural Variation’ document.

Changes made are detailed in the ‘Change Log’ document and other important information about CYP2A6 and the information displayed by PharmVar can be found in the ‘Read Me’ document. All accompanying documents can be accessed at the PharmVar CYP2A6 page at https://www.pharmvar.org/gene/CYP2A6.  

 

Since there are no CPIC guidelines for CYP2A6, the PharmVar CYP2A6 page does not provide information for ‘CPIC clinical function’. The expert panel has, however, compiled a table in the ‘Read Me’ document summarizing function information for selected star alleles.  

 

Lastly, we would like to thank the PharmVar CYP2A6 experts Rachel Tyndale, Alec Langlois, Meghan Chenoweth, Giada Scantamburlo, Charity Nofziger, David Twesigmwe, Rachel Huddart and Andrea Gaedigk for their tireless efforts that made this massive update possible.

Retirement of CYP3A5 alleles in PharmVar

The PharmVar CYP3A5 expert panel has undertaken an extensive review of CYP3A5 allelic variation which led to the retirement of three star alleles, namely CYP3A5*2, *4 and *5. Based on new data, their defining variants were always found together with the CYP3A5*3-defining splice defect (c.219-237) meaning that their variants are part of CYP3A5*3 haplotypes and do not occur on their own as previously assumed.  Specifically, c.1193C>A (formerly defining CYP3A5*2) is now part of the CYP3A5*3.010 suballele, c.599A>G (formerly defining CYP3A5*4) is now part of the CYP3A5*3.009 suballele, and c.432+2T>C is part of the CYP3A5*3.005 suballele which has first been described in 2003 as published as CYP3A5*3G.

This update makes genotype testing and analysis simpler moving forward. CYP3A5*2, *4 and *5 no longer need to be tested as they are tagged by the CYP3A5*3 variant and thereby accurately identified and reported as CYP3A5*3. Note that in the past, a patient who tested homozygous for c.219-237 (CYP3A5*3) and heterozygous for c.1193C>A (CYP3A5*2) may have been reported as having a CYP3A5*3/*3+*2 diplotype.

 

This update on CYP3A5 nomenclature is now shown on the PharmVar CYP3A5 page and is described in more detail in the PharmVar CYP3A5 GeneFocus review published in Clinical Pharmacology and Therapeutics.

 

PharmGKB, CPIC and PharmCAT have been updated accordingly to reflect this change.

Please help secure funding for PGx!!

The ability to predict ahead of time which drugs will be effective for a unique patient and determine which medications may cause patients serious issues, will save lives, improve health care outcomes, and decrease health care costs. Several genes in the human genome play a role in how people respond to medications, including how effective they will be, how quickly medication will be metabolized, and whether a person is likely to experience side effects from a particular drug. A person’s response to a medication, therefore, is impacted by the genetic variants in their those genes.

 

Pharmacogenomic testing evaluates an individual’s genetic makeup to help identify which medication and which dose is right for each patient and hopefully, prevent an adverse drug reaction. Adverse drug events (ADEs) are the most frequently cited significant cause of injury and death among hospitalized patients and can be the result of a drug-drug or drug-gene interaction. Pharmacogenomic testing can save lives by preventing ADEs. According to one estimation, there are more than 2,216,000 serious ADEs recorded in hospitalized patients every year, causing over 106,000 deaths annually, which makes ADEs the fourth leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.

 

In addition, information about drug-gene interactions is not well integrated in patient care and tools that assist with patient care, like electronic alerting systems and electronic health records. Improving pharmacogenomic education and improved record keeping would drive down health care costs. In fact, one four-month long study predicted cost-savings of $1,132 per patient using pharmacogenomic testing and an accompanying alert system as a clinical decision support tool.

 

Congressional Representatives Eric Swalwell and Tom Emmer are introducing the Right Drug Dose Now Act, a bill to improve pharmacogenomics research and patient outcomes. The bill updates the National Action Plan for Adverse Drug Event Prevention; creates a public awareness campaign for adverse drug events and pharmacogenomic testing and a separate health care professional education campaign; creates a program to improve the reporting of adverse drug events through electronic health records; and provides additional funding for NIH to improve research and reporting of adverse drug events through the Genomic Community Resources program.

Please note as part of this bill is the intent is to support with dedicated funding to PGx resources such as PharmGKB, CPIC and PharmVar.

Please reach out to Sarah Shapiro (sarah.shapiro@mail.house.gov) in Representative Swalwell’s office if you or your organization would like to support the Right Drug Dose Now Act. 

Congress needs to hear from us as community. Please help. 

Thank you in advance.  Stay Safe. Be well.

Teri

SLCO1B1 added to PharmVar

PharmVar and PharmGKB are excited to share that SLCO1B1 nomenclature is now maintained by PharmVar. This important drug transporter, also known as OATP1B1, has been shown to facilitate the uptake of stains into the liver. Furthermore, genetic variation has been shown to cause musculoskeletal symptoms impeding statin effectiveness.

Star nomenclature has been used by manuscript authors in the past; allele designations were, however, self-assigned and there was no central repository providing oversight or keeping track of the reported allelic variants. The PharmVar SLCO1B1 gene experts have systematically reviewed and curated all information available in the literature. As the published star allele designations were not necessarily consistent in regard of criteria used for their definition, several alleles were merged and/or revised. In addition, new information gathered by the PharmVar Team were utilized to confirm published allele definitions, fill data gaps to facilitate updating some of the existing definitions, as well as discover novel haplotypes adding star alleles to the collection. Specific details of changes to allele definitions can be found on the PharmVar SLCO1B1 page and on the Change Log tab of the SLCO1B1 Allele Definition Table available from PharmGKB.

PharmGKB, PharmVar and CPIC have coordinated updates to their SLCO1B1 resources to reflect its release in PharmVar. The PharmVar SLCO1B1 gene page includes new allele functions assigned by CPIC as part of its forthcoming update to the guideline on SLCO1B1 and statins. These new PharmVar allele definitions and CPIC functions have been incorporated into the CPIC database and implementation resources for use with the current simvastatin guideline recommendations. All resources available through PharmGKB have also been updated accordingly. Standardized nomenclature for this drug transporter is an important step forward for clinical implementation of stain pharmacogenetics.

NIH Request for Information on Scientific Data Sources

The U.S. National Institutes of Health (NIH) has put out a Request for Information (RFI) on User Experience with Scientific Data Sources and Tools in order to better understand the use of these resources by the scientific community.

We’re asking the pharmacogenomics community to consider responding to the survey and show their support for pharmacogenomics resources like PharmGKB and PharmVar. The RFI closes on October 15.

CYP3A4 now available in PharmVar

PharmVar and PharmGKB are excited to announce that CYP3A4 has been transitioned into the PharmVar database. Check it out here.

Numerous changes and revisions have been made during an extensive curation process including limiting the upstream and downstream regions used for allele definitions and the removal of introns of unknown functional consequence; these revisions caused the retirement of several suballeles or merging of suballeles.

In addition, upgrading to the gene’s current reference sequence (NG_008421.1) caused the c.-392A>G SNP to flip to c.-392G>A; in other words, all alleles that previously had the c.-392A>G SNP now match the RefSeq and are thus no longer showing the variant, while all other alleles gained c.-392G>A. Furthermore, the submission of new data added one novel star allele,CYP3A4*35, several novel suballeles, as well as helped to raise the evidence levels for many alleles from ‘Lim’ to ‘Def’.

Important CYP3A4 information is provided in the ‘Read Me’ document such as reference sequences used and how the PharmVar CAVE tool facilitates comparisons of core allele definitions. All changes and revisions have been summarized in the ‘Change Log’ document. Here we also provide a record of novel haplotypes that have been submitted to PharmVar and have been accepted. 

Finally, a big thank you to all CYP3A4 gene experts for volunteering their time and expertise!

HGVS annotations now available on PharmVar

We are excited to share that PharmVar is now providing HGVS annotations in addition to their more traditional annotations. To accommodate different styles, the Variation Window has been redesigned.

Clicking on any SNV on a PharmVar gene page will activate the variation window. The example shown below is for the CYP2C9*2 variant c.430C>T. This view provides SNV positions across all sequences, the link to the NCBI dbSNP identifier (rs number) as well as SNV frequency. There is also a bar providing the option to display all haplotypes with the selected variant.

The top portion of the variation window displays SNV coordinates according to Human Gene Variation Society (HGVS) nomenclature on the gene, transcript and genome (GRCh37 and GRCh38) levels. Coordinates are displayed as obtained through the NCBI Variation Services. 

The middle portion of the variation window displays SNV positions ‘PharmVar-style’ on the gene, transcript and genome (GRCh37 and GRCh38) levels giving positions for both count modes and detailing the reference and variant nucleotides. 

It is noted that HGVS and ‘PharmVar-style’ positions may differ for insertion/deletion variants in some instances, which is most likely explained by how sequences are aligned. Also, PharmVar displays single nucleotide insertions as ‘ins’ while HGVS displays them as duplications or ‘dup’. Additional details and examples are can be found in the PharmVar ‘Standards’ document. HGVS annotations are also accessible via API services.

PharmVar welcomes any feedback you may have through support@pharmvar.edu. 

CYP2B6 GeneFocus paper published

The latest paper in the PharmVar GeneFocus series, looking at CYP2B6, has now been published in Clinical Pharmacology and Therapeutics.

CYP2B6 is the only member of the CYP2B subfamily to encode a functional enzyme. Variation in this gene impacts the metabolism of several clinically important drugs, including efavirenz (see the CPIC guideline and annotation on PharmGKB), methadone and bupropion. 

The paper gives an overview of CYP2B6 genetic variation and outlines the gene’s previous nomenclature system prior to being catalogued by PharmVar. Details of CYP2B6 resources on PharmGKB and CPIC as well as reference materials for genetic testing are also provided.

CYP2B6 has now been curated into PharmVar, with some alleles revised to remove SNPs with little or no evidence available to show that they caused a change in CYP2B6 function. Users should also note that the *16 and *18 alleles have been consolidated, with *16 now listed as a suballele of *18. All changes have been recorded and can be found on the PharmVar page for CYP2B6.  PharmGKB and CPIC will be updating CYP2B6 information accordingly.

PharmVar would like to thank all members of the CYP2B6 gene expert panel for their efforts in curating this important gene.

CYP3A5 released on PharmVar

PharmVar and PharmGKB are excited to announce that CYP3A5 has been transitioned into the PharmVar database. Variation information has been extensively curated by the PharmVar CYP3A5 gene experts which led to the correction of some allele definitions or reclassification of others. The submission of new data added novel suballeles, as well as helped to raise the evidence levels for several alleles from ‘Lim’ to ‘Def’. Important CYP3A5 information is provided in the ‘Read Me’ document such as reference sequences used and how the PharmVar CAVE tool facilitates comparisons of core allele definitions. All changes and revisions have been summarized in the ‘Change Log’ document. Here we also list all new haplotypes. Check it out at https://www.pharmvar.org/gene/CYP3A5.

And finally, a big thank you to all of the CYP3A5 gene experts who serve on this panel for their hard work.

PharmVar user survey released

The Pharmacogene Variation (PharmVar) Consortium, a central repository for pharmacogene (PGx) variation that focuses on haplotype structure and allelic variation is interested in hearing from the PGx user community regarding their resource.  Please take a couple of minutes to fill out their user survey.

PharmVar GeneFocus paper for CYP2C19 is published

The PharmVar GeneFocus: CYP2C19 paper, the second of the GeneFocus series, has just been published by Clinical Pharmacology & Therapeutics.

PharmVar thanks all CYP2C19 experts as well as the PharmGKB team who have served on this panel and diligently curated this gene and reviewed submissions ever since PharmVar was launched back in 2017. This review provides a general overview of CYP2C19 as well as a deeper dive into the nomenclature.

The GeneFocus also provides a summary of a revision of CYP2C19*1. This revision was introduced to apply PharmVar allele definition criteria consistently across all CYP2C19 haplotypes, as well as to align definitions with the current reference sequence and its recently released LRG. Highlights of the revision include:

·       All but one *1 suballele contained g.80161A>G (I331V), which posed a conflict as this SNP is also present on many other star alleles 

·       To resolve this conflict, *1.001 (previously known as *1A) was revised to *38

o   This haplotype matches the NG_008384.3 RefSeq and LRG_584; therefore, there are no SNVs in the *38 core allele definition

o   All remaining *1 subvariants now contain g.80161A>G (I331V); consequently, g.80161A>G (I331V) has been added to the *1 core allele definition

·       *1 subvariants (with g.80161A>G (I331V)) are more commonly observed than *38

o   Commonly used genotyping platforms do not test for g.80161A>G (I331V) and thus, *1 will be assigned by default

·       The I331V amino acid change does not appear to impact function; therefore, both *1 and *38 are normal function

Changes such as the update from CYP2C19*1.001 to *38 may be viewed as ‘interruptive’. However, having standardized nomenclature that is consistently applied will greatly benefit the research and clinical PGx communities moving forward. The revision can now be found on the PharmVar page for CYP2C19.

PGRN Transition

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is becoming an independent scientific society on July 1, 2020. The deadline for becoming a founding member has been extended. If you are interested in joining, please visit www.pgrn.org.

On behalf of all of the NIH PGRN funded investigators, we thank NIH for their past support, particularly our original program officer, Dr. Rochelle Long (NIGMS Director, Division of Pharmacology, Physiology and Biological Chemistry).

Update 6/29/2020 The inaugural Research In Progress (RIPS) webinar from the PGRN society will be given by Alan Shuldiner, MD, on Friday July 17 at 11am Eastern time. Dr. Shuldiner will speak on "Building bridges between industry, academia, health care systems and communities to advance Precision Medicine".

From Friday August 14, RIPS webinars will be held on the second Friday of every month at 11am Eastern time for all PGRN members. A schedule of upcoming RIPS webinars can be found here. If you are interested in joining the PGRN, you can become a member at www.pgrn.org.

Dr. Stuart Scott joins Stanford

We are pleased to announce that Dr. Stuart Scott will be joining Stanford University as a Professor in the Department of Pathology effective 1 September 2020. In addition, Dr. Scott will be Laboratory Director of the Stanford Medicine Clinical Genomics Program. Dr. Scott is moving from the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai and Sema4 (previously the Mount Sinai Genetic Testing Laboratory). He is certified by the American Board of Medical Genetics and Genomics in both Clinical Molecular Genetics and Clinical Cytogenetics and Genomics. Dr. Scott’s research interests include pharmacogenomics (PGx), cytogenomics, epigenomics, and the implementation of genomic medicine. He has long standing collaborations with Stanford’s multi-institutional efforts in PGx including PharmGKB, CPIC, PharmVar and PharmCAT.