MYH7 Variant “Bake-Off”

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MYH7 Variant “Bake-Off”
CLINGEN’S
CARDIOVASCULAR DISEASE WORKING GROUP
A Worldwide Effort to Unify Variant and Gene Curation
Approaches
Birgit Funke, PhD, FACMG
On behalf of the Cardiovascular Disease Working Group
WORKING GROUP GOALS
Network with disease experts and testing laboratories around
the world to centralize and curate genetic knowledge for clinical
applications
http://clinicalgenome.org/about/working-groups/clinical-domain/cardiovascular/
KEY ELEMENTS AND PLAYERS
CLINVAR
LAB 1
LAB2
EXPERT
WORKING
GROUPS
LAB3
Labs
Labs
Labs
Labs
Experts
Experts
Experts
Experts
OTHER LABS AND EXPERTS
CARDIOVASCULAR DOMAIN WG MEMBERS
ClinGen
Channelopathy
Co-Chairs
Cardiomyopathy
NHGRI
Aortopathy
http://clinicalgenome.org/about
/working-groups/clinicaldomain/cardiovascular/
TOWARDS A
WORLD WIDE CARDIOVASCULAR DISEASE NETWORK
CAN. TESTING LABS
STANFORD
NETHERL
ICELAND
TORONTO
U.S. HARVARD/LMM
NETHERLANDS
GREAT BRITAIN
GB
OHIO STATE
GB
OTHER TESTING LABS
(Australia, India, Finland, G.B./Singapore)
ITALY
ITALY
U.S. TESTING LABS
INDIA/BANGALORE
SHaRe
SINGAPORE
• Egypt
• Asia
• Middle East
OTHER
NETWORKS
BRAZIL
WORD OF MOUTH
REFERRALS
EXISTING CLINVAR
SUBMITTERS
CMP CHNL AORT
CLINGEN
WORKGROUP
VCGS
CENTENARY
IMPACT ON CLINVAR SUBMISSIONS
MYH7
•
•
15 ClinVar Submitters (1520 variants submitted)
14% (216/1520) solicited by working group activities
• Challenge: submitters often do not have the capacity and
expertise to convert their variants into ClinVar-ready format…
PILOT 1
CLINVAR
LAB 1
LAB2
EXPERT
WORKING
GROUPS
LAB3
Labs
Labs
Labs
Labs
Experts
Experts
Experts
Experts
OTHER LABS AND EXPERTS
CLINVAR DRIVEN HARMONIZATION
CLINVAR
Sequential review of ClinVar discrepancies
LAB
1
LAB
2
Need Clinical Expert
1/80 variants (GLA)
• Lab 1 = VUS
• Lab2 = Lik Path
n = 80
LAB1
n= 40
LAB2
n= 30
Call
Classification Rule Differences
Resolvable
• (e.g. Differences in
frequency cut-offs)
Key lesson!!
Difficult to resolve
• Lab1: Silent = VUS
• Lab2: Silent = Likely benign
Reason = reporting differences
• Lab1: VUS + not on report
• Lab2: Lik Ben + on report
KEY ELEMENTS AND PLAYERS
CLINVAR
LAB 1
LAB2
EXPERT
WORKING
GROUPS
LAB3
Labs
Labs
Labs
Labs
Experts
Experts
Experts
Experts
OTHER LABS AND EXPERTS
ACTIVE WORKING GROUP PROJECTS
Variant curation
• Use high impact genes to develop framework
• Cardiomyopathy: MYH7
• Channelopathy: KCNQ1
• Use ACMG's new rules as a baseline
Gene curation
• Curate evidence for gene-disease relationships
• Use ClinGen’s clinical validity scheme
MYH7 CURATION
Associated disorders are prevalent, high detection rates, severe health outcomes
Disorder
Prevalence
Detection Rate
HCM
1/500
25%
DCM
1/250 – 1/2500
5%
Approach
1.
2.
3.
4.
Mini-pilot (compare ACMG rules to existing rules)
Detailed review and adaptation of ACMG rules
Validate rules + develop framework and process
Implement: curate all variants in ClinVar
Can lead to SCD
PHASE 1 - CURATION BAKE-OFF
MYH7
Variant
Instit. Classification
LMM
Stanford
ACMG Classification
LMM Stanford
p.Arg369Gln
Pathogenic
Likely disease causing
Lik. Path
Lik. Path
p.Gly584Arg
Lik. Pathogenic
Likely disease causing
VUS
Lik. Path
p.Arg663His
Pathogenic
Very likely disease causing
VUS
Lik. Path
p.Arg719Trp
Pathogenic
Very likely disease causing
Path
Path
p.Arg723Cys
Pathogenic
Very likely disease causing
Lik. Path
Lik. Path
p.Gly741Trp
Lik. Pathogenic
Likely disease causing
VUS
Lik. Path
p.Leu908Val
Pathogenic
Very likely disease causing
Lik. Path
Lik. Path
p.Asn1327Lys
Likely Benign
VUS, probably benign
(possibly modifier)
VUS
Lik. Ben
p.Lys1459Asn
VUS-5
Likely disease causing
VUS
VUS
p.Arg1530X
VUS-5
VUS
VUS
VUS
PHASE 2: ADAPTING ACMG RULES
EXAMPLE
ACMG: Benign if MAF>5%
Which threshold is appropriate for MYH7?
FREQUENCY THRESHOLDS
MISSENSE
Contributor
ACMG 2015
Committee?
N/A
Subgroup
Julie DeBacker
LMM
Ray/Ana
Euan/Colleen
Peter/Jan
Lori Bean
Tom Callis
Desiree DuSart
Committee
Committee
Committee
Committee
Committee
EGL
Transgenomic
VCGS (Australia)
Aortopathy
CMP
CMP
CMP
CMP
-------
BENIGN
any cohort (small)
large cohorts
MAF # alleles # chrom MAF # alleles # chrom
5%
n/a
n/a
2%
3%
1%
1%
2%
n/a
5
n/a
n/a
4
n/a
167 1%
n/a
n/a
200 0.5%
0.5%
0.2%
n/a
30
3000
25
n/a
5000
n/a
THRESHOLDS IN CLINICAL USE RANGE FROM
2
400
0.2% TO 3%
1%
n/a
APPROACHES
A ) Use known pathogenic variants
– Check large “control cohorts” (e.g. ExAC) for max frequency
– Variants with MAF above max frequency are unlikely
disease causing
B ) Use prevalence, penetrance and detection rate
– Variant is not disease causing when present in a control
cohort at a frequency that is inconsistent with mode of
inheritance + disease prevalence and penetrance
USING PENETRANCE AND PREVALENCE
Gene
Contribution
Condition
Prevelance
(aka affected carriers)
Penetrance
Affected carriers
Unaffected carriers
Total carrier rate (MYH7)
MYH7
5%
DCM
1/300
1/600
from Pugh paper (with VUS-5 for ALL cases; all = 3-5%, adults = 2-3%, peds = 4-6%, infants = 5-9%)
people
chromosomes
Unaffected carriers (present in control cohorts)
[ 1/600 x 0.05 x (1-penetrance) ]
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0% 100.0%
0.0083% 0.0083% 0.0083% 0.0083% 0.0083% 0.0083% 0.0083% 0.0083% 0.0083% 0.0083%
0.0750% 0.0333% 0.0194% 0.0125% 0.0083% 0.0056% 0.0036% 0.0021% 0.0009% 0.0000%
0.0833% 0.0417% 0.0278% 0.0208% 0.0167% 0.0139% 0.0119% 0.0104% 0.0093% 0.0083%
•
At 10% penetrance the total % of unaffected carriers of MYH7 variants is
estimated to be 0.08%
•
Could safely assume that a variant with a MAF of 0.1% is benign
• Penetrance not that low
• Allelic heterogeneity is pronounced
P
M
PHASE 3: TEST MODIFIED ACMG RULES
Use ClinVar as a source to design medium sized pilot
• Top 3 submitters: 846 unique variants
• Differences in distribution of classifications
Lab 3
Lab 2
Lab 1
MYH7 Discrepancy Summary (ClinVar)
Multiple
Submitters
(concordant), 118
Single Submitter,
663
Multiple
Submitters
(Discordant), 144
VUS vs Lik
Path/Path, 109
Ben/Lik
Ben vs
VUS, 32
Ben/Lik Ben vs Lik
Path/Path, 3
Next steps:
• Structured curation (recruited 3 additional curators)
• Engage with ClinVar submitters
Courtesy of Steven Harrison
FACILITATE HARMONIZATION
CLINVAR
LAB 1
LAB2
Engage ClinVar
submitters
EXPERT
WORKING
GROUPS
LAB3
Labs
Labs
Labs
Labs
Experts
Experts
Experts
Experts
OTHER LABS AND EXPERTS
GENE CURATION
Evidence Level
DEFINITIVE
STRONG
MODERATE
LIMITED
NO EVIDENCE
Evidence Description
The role of this gene in this particular disease has been repeatedly demonstrated in both the
research and clinical diagnostic settings, and has been upheld over time. No valid evidence has
emerged that contradicts the role of the gene in the specified disease.
There is strong evidence by at least two independent studies to support a causal role for this gene
in this disease, such as:
•Strong statistical evidence demonstrating an excess of pathogenic variants in affected individuals
as compared to appropriately matched controls
•Multiple pathogenic variants within the gene in unrelated probands with several different types of
supporting experimental data. The number and type of evidence might vary (eg. fewer variants
with stronger supporting data, or more variants with less supporting data)
In addition, no valid evidence has emerged that contradicts the role of the gene in the noted
disease.
There is moderate evidence to support a causal role for this gene in this disease, such as:
•At least 3 unrelated probands with pathogenic variants within the gene, with some supporting
gene-level experimental data.
The role of this gene in this particular disease may not have been independently reported, but no
valid evidence has emerged that contradicts the role of the gene in the noted disease.
There is limited evidence to support a causal role for this gene in this disease, such as:
•Fewer than three observations of a pathogenic variant within the gene
•Multiple variants reported in unrelated probands but without sufficient evidence for
pathogenicity
No evidence reported for a causal role in disease.
DISPUTED
Valid evidence of approximate equivalent weight exists both supporting and refuting a role for this
gene in this disease.
EVIDENCE AGAINST
Evidence refuting the role of the gene in the specified disease has been reported and significantly
outweighs any evidence supporting the role.
Courtesy of ClinGen’s gene curation group (co-chairs Jonathan Berg/Christa Martin)
APPROACH
Core list of cardiomyopathy genes
ClinGen curators
& liaisons
Domain Expert
Reviewers
HCM DCM ARVC
ClinGen
Cardiovascular
WG
domain experts to
liaise with ClinGen
curators and prereview curation
Clinical experts
finalize
LESSONS LEARNED
Challenges and bottlenecks
•
ClinVar submissions are not trivial for many
•
WG members cannot get the work done alone - difficult to
recruit experts who have interest + are willing to work for
the greater good
•
Variant curation rules are somewhat tied to how clinical
labs choose to report variants
But
• There is tremendous interest in the greater community
to be part of this!
ACKNOWLEDGEMENTS
ClinGen Cardiovascular WG
•
•
•
•
•
•
•
•
•
•
•
•
Ray Hershberger •
Euan Ashley
•
Birgit Funke
•
Laura Milko
•
Jonathan Berg •
Rajarshi Gosh •
Colleen Caleshu •
Melanie Care
•
Julie DeBacker •
Harry Dietz
•
Mike Gollob
•
Jodie Ingles
•
Other ClinGen and LMM Members
Jan Jongbloed
• Heidi Rehm (LMM and ClinGen)
Melissa Kelly
• Steven Harrison (LMM and ClinGen)
Bart Loyes
• Danielle Azzariti (LMM and ClinGen)
Bill McKenna
• Jillian Buchan (LMM)
Diana Milewicz
Ana Morales
Emory Genetics Lab
Valeria Novelli
Silvia Pirori
• Lori Bean
Chris Semsarian • Madhuri Hegde
Amy Sturm
Peter van Tintelen
Arthur Wilde
THANKS!

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