Thoracic aortic aneurysm and dissection

Gene: ABL1

Green List (high evidence)

ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase)
EnsemblGeneIds (GRCh38): ENSG00000097007
EnsemblGeneIds (GRCh37): ENSG00000097007
OMIM: 189980, Gene2Phenotype
ABL1 is in 11 panels

6 reviews

Kate Thomson (Oxford University Hospitals Foundation Trust)

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. This gene did not achieve a consensus Green rating; however, the group agreed that the existing evidence (published and in-house data) was sufficient to support inclusion in this panel.
Created: 9 Dec 2019, 1:19 p.m. | Last Modified: 9 Dec 2019, 1:19 p.m.
Panel Version: 0.55

Ivone Leong (Genomics England Curator)

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.
Created: 18 Nov 2019, 4:33 p.m. | Last Modified: 18 Nov 2019, 4:33 p.m.
Panel Version: 0.35

James Eden (Manchester)

I don't know

Gene not currently tested on Manchester cardiac gene panel. 6 variants listed on HGMD (accessed 24/09/2019), two of which from Wang et al Nature Genetics 2017. ClinGen Knowledge Base: gene not curated (accessed 24/09/2019).
Created: 25 Sep 2019, 9:07 a.m. | Last Modified: 25 Sep 2019, 9:07 a.m.
Panel Version: 0.30

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Congenital heart defects and skeletal malformations syndrome, 617602

Publications

Rebecca Whittington (South West GLH)

Green List (high evidence)

617602 Congenital heart defects and skeletal malformations syndrome - includes ASD, VSD, aortic root dilation and coarctation of the aorta in addition to other syndromic connective tissue phenotypes; only two variants associated with this phenotype in HGMD, both from same publication
Created: 25 Mar 2019, 4:30 p.m.
Wang et al 2017 Nat Genet 49:613 PMID 28288113 describe two variants: c.734A>G (p.Tyr245Cys) found de novo in 5 individuals from 3 families (segregates with disease in two affected individuals from each of 2 families) and c.1066G>A (p.Ala356Thr) found de novo in a single family. Both variants are well conserved and affect the kinase domain. Neither have any gnomAD frequency and both are reported as pathogenic by more than one source on ClinVar.
Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Rebecca Foulger (Genomics England curator)

Added 'missense' tag.
Created: 6 Dec 2018, 8:46 p.m.
Comment on list classification: Updated rating from Grey to Green. Gene was added by Chris Buxton based on evidence in PMID:28288113. Although CB rated the gene Red, mild aortic root dilation/mild coarctation of the aorta is seen in patients from 3 families. Therefore phenotype is relevant to panel and sufficient unrelated cases to support diagnostic rating, as agreed by Helen Brittain, clinical fellow.
Created: 6 Dec 2018, 8:46 p.m.
Comment on mode of pathogenicity: Seleced 'LOF do not cause this phenotype' on advice from Helen Brittain, Clinical Fellow, in view of the postulated gain of function mechanism (two recurent missense variants).
Created: 6 Dec 2018, 8:43 p.m.
Wang et al. 2017 (PMID:28288113) report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo in 3 individuals (families 1-2) and in family 3, the variant was seen in the affected father and daughter. Heart defects include aortic root dilatation and/or coarctation.
Created: 6 Dec 2018, 8:41 p.m.

Chris Buxton (North Bristol NHS Trust)

Red List (low evidence)

Gain of function variants in this gene are described by Wang (2017, PMID 28288113) as a ddx for TGFB overexpression pathway disorders, eg Loeys Dietz, Shprintzen Goldberg, Marfan syndrome.

Wang X et al., Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. Nat Genet. 2017 Apr;49(4):613-617.
Sources: Literature
Created: 22 Nov 2018, 9:53 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital finger flexion contractures (HP:0005879); Congenital septal defect (HP:0004760); Generalized joint laxity (HP:0002761); Ascending aortic dilation (HP:0004970); Scoliosis (HP:0002650); Failure to thrive in infancy (HP:0001531); Hypospadias (HP:0000047); Pectus excavatum (HP:0000767)

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • South West GLH
Phenotypes
  • Failure to thrive in infancy (HP:0001531)
  • Generalized joint laxity (HP:0002761)
  • Ascending aortic dilation (HP:0004970)
  • Congenital finger flexion contractures (HP:0005879)
  • Hypospadias (HP:0000047)
  • Pectus excavatum (HP:0000767)
  • Congenital heart defects and skeletal malformations syndrome, 617602
  • Scoliosis (HP:0002650)
  • Congenital septal defect (HP:0004760)
OMIM
189980
Clinvar variants
Variants in ABL1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

9 Dec 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: abl1 has been classified as Green List (High Evidence).

18 Nov 2019, Gel status: 2

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: ABL1 were set to

18 Apr 2019, Gel status: 2

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Ellen McDonagh (Genomics England Curator)

gene: ABL1 was added gene: ABL1 was added to GMS FTAAD placeholder panel. Sources: Expert Review Amber,South West GLH Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ABL1 were set to Failure to thrive in infancy (HP:0001531); Generalized joint laxity (HP:0002761); Ascending aortic dilation (HP:0004970); Congenital finger flexion contractures (HP:0005879); Hypospadias (HP:0000047); Pectus excavatum (HP:0000767); Congenital heart defects and skeletal malformations syndrome, 617602; Scoliosis (HP:0002650); Congenital septal defect (HP:0004760)