Steven Harrison sharrisonbwhharvardedu March 22 2018 SVI Updates Reputable source PP5BP6 paper Bayes paper PVS1 LOF recommendation PS2PM6 De novo recommendation Reputable Source Letter to the Editor ID: 931627
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Slide1
BioCuration Call:Sequence Variant Interpretation WG Update
Steven Harrison (
sharrison@bwh.harvard.edu
)
March 22, 2018
Slide2SVI
Updates
Reputable source (PP5/BP6) paper
Bayes paper
PVS1 (
LOF
) recommendation
PS2/PM6 (De novo) recommendation
Slide3Reputable Source Letter to the Editor
(
PMID
: 29543229)
Slide4Slide5PMID
: 29543230
Slide6Post_P
: >0.99 = Pathogenic
Post_P
: 0.9-0.99 = Likely Pathogenic
Post_P
: 0.1-0.001 = Likely Benign
Post_P
: <0.001 = Benign
Slide7From ACMG/AMP Paper:
From Bayes/
SVI
Paper:
Slide8Slide9Classification Calculator –
Supp
Table S1
Slide10Posting recommendations as they are finalized – and versioning each recommendation
Linking to approved EP specified ACMG/AMP criteria
Slide11Slide12Slide13Slide14FLOWCHART ASSUMES LOSS OF FUNCTION IS AN ESTABLISHED DISEASE MECHANISM
Slide15Slide16Slide17Functional studies have shown that start re-initiation can be very robust occurring at alternate ATG or non-ATG sites downstream and even upstream of the lost original start site
Slide18p.M122
GAA
c.1A>G =
PVS1_Moderate
>1 pathogenic variant upstream of next potential start site (p.122)
Slide19Slide20PAH c.442-1G>A =
PVS1
The ± 1,2 splice variant is predicted to have an out-of-frame consequence, i.e. affects an exon whose length is indivisible by 3.
AND
This change is predicted to cause
NMD
, i.e. the variant is NOT in the last intron.
AND
The affected exon is NOT alternatively spliced from the major or biologically relevant transcript(s).
Slide21Slide22PTEN
c.1003C>T (p.Arg335Ter) –
PVS1_Strong
This change is NOT likely to cause
NMD
(variant is in second to last exon)
AND
The truncated or altered region is critical to protein function based on experimental evidence or presence of non-truncating pathogenic variants (
PTEN
group defined p.Asp375 as boundary for critical region).
Slide23Slide24Pilot Set – PVS1 variants
45
LOF
-type variants
WGs
asked to use PVS1 flowchart
Agreed with evidence level for 89% (40/45)
For all discordant,
WGs
wanted to give variant a higher evidence level
Slide25Slide26Slide27Next Steps for PVS1
Manuscript in process for PVS1 specification
Guidance for combining PVS1 with other ACMG/AMP criteria
Functional assays?
Lowering weight of evidence when gene/disease validity is not Strong or Definitive
Slide28Slide29Slide30SVI Recommendation for De Novo Criteria
The Sequence Variant Interpretation (SVI) Working Group proposes a point-based system to determine the strength of
de novo
evidence (ACMG/AMP criteria codes PS2 and PM6) based upon three parameters:
confirmed
versus
assumed
status
phenotypic consistency
number of
de novo
observations
Slide31Slide32A patient with early infantile epileptic encephalopathy and a confirmed
de novo
SIK1
variant is awarded 1 point
(as the patient’s phenotype is consistent with the gene but not highly specific).
Total points: 1
Moderate (PS2_Moderate)
Slide33A patient with
nonsyndromic
intellectual disability and a confirmed
de novo
ASH1L
variant is awarded 0.5 points
(as the variant is confirmed
de novo
and patient’s phenotype is consistent with the gene but not highly specific and there is significant evidence of genetic heterogeneity).
Total points: 0.5
Supporting (PS2_Supporting)
Slide34A patient with developmental delay but no other features of Cornelia de Lange syndrome and an assumed
de novo
NIPBL
variant is awarded zero points as this phenotype is not consistent with the gene/disease association.
If this patient was the only
de novo
occurrence for the variant, then no
de novo
criteria are applied.
Total points: 0
Slide35A de novo
NIPBL
variant in 3
probands
….
Confirmed
de novo
in one patient with Cornelia de Lange syndrome (
2
pt
)
Assumed
de novo
in one patient with Cornelia de Lange syndrome (
1
pt
)
Assumed
de novo
in another patient with Cornelia de Lange syndrome (
1
pt
)
Total of 4 points (2+1+1) =
VeryStrong
Slide36PM3 (in trans) recommendation nearing completion
Quantitative approach similar to de novo (PS2/PM6)
Slide37SVI
Team PVS1 Examples
Leslie G. Biesecker (co-chair)
Steven Harrison (co-chair)
Ahmad Abou Tayoun
Jonathan Berg
Steven E. Brenner
Fergus Couch
Garry Cutting
Sian Ellard
David Goldstein
Marc Greenblatt
Matt
Hurles
Peter Kang
Izabela Karbassi
Rachel
Karchin
Jessica Mester
Robert L. Nussbaum
Anne O'Donnell-Luria
Tina Pesaran
Sharon Plon
Heidi Rehm
Sean
Tavtigian
Scott Topper
Melanie Care
Rachid Karam
Jessica Mester
Tina Pesaran
Catherine Rehder
Amanda Thomas