Hereditary haemorrhagic telangiectasia

Gene: GDF2

Amber List (moderate evidence)

GDF2 (growth differentiation factor 2)
EnsemblGeneIds (GRCh38): ENSG00000263761
EnsemblGeneIds (GRCh37): ENSG00000128802
OMIM: 605120, Gene2Phenotype
GDF2 is in 3 panels

5 reviews

Matthew Edwards (Clinical Genetics & Genomics Lab, Royal Brompton & Harefield NHS Trust)

I don't know

On CGGL Royal Brompton HHT diangostic panel. Limited evidence in literature, more required.
Created: 22 Sep 2019, 8:19 p.m. | Last Modified: 22 Sep 2019, 8:19 p.m.
Panel Version: 1.51

Phenotypes
OMIM: 615506 Telangiectasia, hereditary hemorrhagic, type 5

Publications

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

I don't know

From GMS Respiratory Specialist Test Group webex call 18th Jan 2019 : keep classified as amber on basis of 3 cases (see review)
Created: 21 Jan 2019, 11:21 a.m.
Initial gene list and info collated by Ian Berry Leeds Genetics Laboratory November 2018 on behalf of the GMS Respiratory specialist test group. Gene Symbol submitted GDF2; Suggested initial gene rating: Green; Evidence for inclusion: OMIM HHT gene; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given
Created: 6 Dec 2018, 12:36 p.m.

Ellen McDonagh (Genomics England Curator)

Comment on list classification: Discussed internally and decided to keep as amber as PMID:23972370 only provides evidence for inheritance in one proband. Awaiting more evidence for familial segregation.
Created: 14 Dec 2016, 11:30 a.m.
Comment on list classification: Changed status to amber due to the comment from reviewer that all variants reported are missense.
Created: 14 Dec 2016, 10:08 a.m.

Sarah Leigh (Genomics England Curator)

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P / DD. At least four variants reported in cases, one of which is classified as a variant of unknown significance
Created: 13 Dec 2016, 12:19 p.m.
In vitro assays and zebra fish model evidence supports involvement of GDF2 in HHT, with variants having different effects
Created: 12 Dec 2016, 2:49 p.m.

Claire Shovlin (Imperial College London)

Red List (low evidence)

The initial description was of novel pathogenic missense substitutions in three (of 191) unrelated patients clinically suspected to have hereditary haemorrhagic telangiectasia (HHT), but with no pathogenic variants identified in ENG, ACVRL1, or SMAD4 (PMID: 23972370). The three probands were considered to display some phenotypic overlap with HHT. A further missense substitution (assigned as a variant of unknown significance) was identified in a screen of 93 ENG, ACVRL1, and SMAD4 negative unrelated individuals clinically suspected to have HHT (PMID: 27081547).

HHT is usually caused by a pathogenic variant in either ENG or ACVRL1, with pathogenic missense substitutions more commonly found in ACVRL1. ExAc Constraint metrics [http://biorxiv.org/content/early/2016/05/10/030338 ] suggest GDF2 exhibits better toleration of missense substitutions than ACVRL1, and similar toleration to ENG: Missense GDF2 expected number of ExAc variants 165.7, observed 158, z=0.29 (contrast ACVRL1 expected 199.6, observed 132 z=2.34, but ENG expected 235.9, observed 223, z=0.41).
Created: 13 Nov 2016, 10:51 p.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • NHS GMS
  • Expert Review Amber
  • Emory Genetics Laboratory
  • Expert Review
  • UKGTN
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Telangiectasia, hereditary hemorrhagic, type 5 615506
OMIM
605120
Clinvar variants
Variants in GDF2
Penetrance
Complete
Publications
  • 23972370 - 3 unrelated probands with no variants identified in ENG, ACVRL1, and SMAD4
  • 27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4
  • 25674101 - review from the same authors as PMID:23972370
Panels with this gene

History Filter Activity

6 Dec 2018, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to GDF2.

14 Dec 2016, Gel status: 2

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

14 Dec 2016, Gel status: 2

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

14 Dec 2016, Gel status: 4

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for GDF2 were set to 23972370 - 3 unrelated probands with no variants identified in ENG, ACVRL1, and SMAD4; 27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4; 25674101 - review from the same authors as PMID:23972370

14 Dec 2016, Gel status: 4

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for GDF2 were set to 23972370; 27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4; 25674101

14 Dec 2016, Gel status: 4

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for GDF2 were set to 23972370; 27081547; 25674101

12 Dec 2016, Gel status: 4

panel promoted to version 1

Sarah Leigh (Genomics England Curator)

Promoted to V1 (12th December 2016)

12 Dec 2016, Gel status: 4

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

12 Dec 2016, Gel status: 3

Upload gene information

Sarah Leigh (Genomics England Curator)

GDF2 was added to Hereditary haemorrhagic telangiectasiapanel. Sources: Emory Genetics Laboratory,Expert Review,UKGTN,Radboud University Medical Center, Nijmegen

12 Dec 2016, Gel status: 1

clearsources

Sarah Leigh (Genomics England Curator)

GDF2All sources for gene: GDF2 were removed

12 Dec 2016, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for GDF2 were set to 23972370; 27081547; 25674101; 27081547

12 Dec 2016, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for GDF2 were set to 23972370; 27081547; 25674101

12 Dec 2016, Gel status: 1

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for GDF2 were set to Telangiectasia, hereditary hemorrhagic, type 5 615506

12 Dec 2016, Gel status: 1

Set Mode of Inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for GDF2 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

12 Dec 2016, Gel status: 1

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

12 Dec 2016, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for GDF2 were set to 23972370; 27081547

12 Dec 2016, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for GDF2 were set to 23972370

30 Oct 2015, Gel status: 2

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

GDF2 was added to Hereditary haemorrhagic telangiectasiapanel. Source: Emory Genetics Laboratory Model of inheritance for gene GDF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

30 Oct 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

GDF2 was created by ellenmcdonagh

30 Oct 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

GDF2 was added to Hereditary haemorrhagic telangiectasiapanel. Sources: Radboud University Medical Center, Nijmegen