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BioCuration  Call: Sequence Variant Interpretation WG Update BioCuration  Call: Sequence Variant Interpretation WG Update

BioCuration Call: Sequence Variant Interpretation WG Update - PowerPoint Presentation

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BioCuration Call: Sequence Variant Interpretation WG Update - PPT Presentation

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

variant novo patient pvs1 novo variant pvs1 patient evidence points confirmed ps2 recommendation criteria svi acmg amp paper cornelia

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Presentation Transcript

Slide1

BioCuration Call:Sequence Variant Interpretation WG Update

Steven Harrison (

sharrison@bwh.harvard.edu

)

March 22, 2018

Slide2

SVI

Updates

Reputable source (PP5/BP6) paper

Bayes paper

PVS1 (

LOF

) recommendation

PS2/PM6 (De novo) recommendation

Slide3

Reputable Source Letter to the Editor

(

PMID

: 29543229)

Slide4

Slide5

PMID

: 29543230

Slide6

Post_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

Slide7

From ACMG/AMP Paper:

From Bayes/

SVI

Paper:

Slide8

Slide9

Classification Calculator –

Supp

Table S1

Slide10

Posting recommendations as they are finalized – and versioning each recommendation

Linking to approved EP specified ACMG/AMP criteria

Slide11

Slide12

Slide13

Slide14

FLOWCHART ASSUMES LOSS OF FUNCTION IS AN ESTABLISHED DISEASE MECHANISM

Slide15

Slide16

Slide17

Functional 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

Slide18

p.M122

GAA

c.1A>G =

PVS1_Moderate

>1 pathogenic variant upstream of next potential start site (p.122)

Slide19

Slide20

PAH 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).

Slide21

Slide22

PTEN

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).

Slide23

Slide24

Pilot 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

Slide25

Slide26

Slide27

Next 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

Slide28

Slide29

Slide30

SVI 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

Slide31

Slide32

A 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)

Slide33

A 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)

Slide34

A 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

Slide35

A 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

Slide36

PM3 (in trans) recommendation nearing completion

Quantitative approach similar to de novo (PS2/PM6)

Slide37

SVI

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