Limb girdle muscular dystrophy

Gene: TTN

Green List (high evidence)

TTN (titin)
EnsemblGeneIds (GRCh38): ENSG00000155657
EnsemblGeneIds (GRCh37): ENSG00000155657
OMIM: 188840, Gene2Phenotype
TTN is in 18 panels

7 reviews

Ellen McDonagh (Genomics England Curator)

Comment on list classification: Promoted from Red to Green due to overall the majority of reviews are Green, and there is a consensus that although classifying variants in this is difficult, additional phenotyping studies can aid in confirmation of diagnosis and that this gene should be included on this panel.
Created: 28 Nov 2019, 3:28 p.m. | Last Modified: 28 Nov 2019, 3:28 p.m.
Panel Version: 1.102

Chiara Marini Bettolo (NUTH)

Green List (high evidence)

Disese spectrum can be very variable from congenital myopathy, cardiomyopathy, distal weakness, HMERF to LGMD. Known form of LGMD2J or LGMDR10
Created: 21 Oct 2019, 1:27 p.m. | Last Modified: 21 Oct 2019, 1:27 p.m.
Panel Version: 1.97
Loss of function variants and missense variants are also reported as pathogenic. The analysis of titin variants is more complex than this proforma allows for
Created: 10 May 2019, 2:15 p.m.

Phenotypes
Limb-girdle muscular dystrophy; distal myopathy; HMERF; dilated cardiomyopathy; arthrogryposis; myofibrillar myopathy

Mode of pathogenicity
Other

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

Louise Daugherty (Genomics England Curator)

I don't know

Review and rating from Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.
Created: 30 Apr 2019, 11:45 a.m.

Natalie Forrester (SWGLH - Bristol Genetics)

Red List (low evidence)

Complex phenotype, unlikely pure LGMD. Paper describes variety. PMIDL12145747 - large Finnish family with LGMD2J. Identified homozygosity for an 11-bp deletion/insertion in the last exon (exon 363). Family members affected with the milder adult-onset TMD phenotype were heterozygous for the TTN deletion.
Created: 30 Apr 2019, 11:24 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Muscular dystrophy, limb-girdle, type 2J, 608807

Publications

Elizabeth Harris (Newcastle upon Tyne NHS Foundation Trust)

Green List (high evidence)

Currently only recurrent HMERF associated mutations are reported by this lab but truncating variants are also of great clinical interest. Difficulty classifying variants in titin should not be a reason not to include this gene as additional phenotyping studies such as muscle MRI, biopsy review and protein analysis is often extremely helpful in confirming or refuting the diagnosis.
Created: 29 Mar 2019, 1:14 p.m.
Loss of function variants are simpler to classify but missense variants are also reported as pathogenic. The analysis of titin variants is more complex than this proforma allows for
Created: 26 Mar 2019, 4:54 p.m.

Phenotypes
Limb girdle muscular dystrophy; Distal myopathy; Myofibrillar myopathy; Congenital myopathy; dilated cardiomyopathy

Publications

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

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Listed as associated with Limb Girdle Muscular Dystrophy by Gene Advisor (June 2016), Steve Abbs
Created: 27 Jul 2016, 8:27 a.m.
Comment on phenotypes: Also associated with Cardiomyopathy, dilated, 1G 604145; Cardiomyopathy, familial hypertrophic, 9 613765; Myopathy, early-onset, with fatal cardiomyopathy 611705; Myopathy, proximal, with early respiratory muscle involvement 603689; Tibial muscular dystrophy, tardive 600334
Created: 26 Jul 2016, 1:52 p.m.
Comment when marking as ready: Associated with phenotype in OMIM, not G2P (for this phenotype). Found in 3/4 sources. One reviewer recommends Amber. Three variants reported one each in Finnish, French and Han Chinese families (26392295; 12145747), not very strong evidence for the pathogenicity of these variants.
Comment from Emma Clement: Predominantly myopathy gene (in terms of muscle phenotype) really but I think lots of mutations in this will have been missed as it it not screened due to size. I think you could leave this orange for now
Created: 14 Jun 2016, 10:26 a.m.

Ellen Thomas (Genomics England Curator)

Comment on list classification: A particular homozygous 11bp deletion has been found in a small number of patients with LGMD. Many other muscle phenotypes plus cardiomyopathy associated with monoallelic and biallelic mutations in this highly polymorphic gene.
Created: 29 May 2016, 2:51 p.m.

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Yorkshire and North East GLH
  • NHS GMS
  • South West GLH
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Muscular dystrophy, limb-girdle, type 2J, 608807
  • Limb girdle muscular dystrophy
  • Distal myopathy
  • Myofibrillar myopathy
  • Congenital myopathy
  • dilated cardiomyopathy
  • HMERF
  • arthrogryposis
OMIM
188840
Clinvar variants
Variants in TTN
Penetrance
Complete
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

28 Nov 2019, Gel status: 3

Set mode of pathogenicity

Ellen McDonagh (Genomics England Curator)

Mode of pathogenicity for gene: TTN was changed from to Other

28 Nov 2019, Gel status: 3

Entity classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

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

13 May 2019, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Yorkshire and North East GLH was added to TTN.

13 May 2019, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: TTN were changed from Muscular dystrophy, limb-girdle, type 2J, 608807; Limb girdle muscular dystrophy; Distal myopathy; Myofibrillar myopathy; Congenital myopathy; dilated cardiomyopathy to Muscular dystrophy, limb-girdle, type 2J, 608807; Limb girdle muscular dystrophy; Distal myopathy; Myofibrillar myopathy; Congenital myopathy; dilated cardiomyopathy; HMERF; arthrogryposis

30 Apr 2019, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: TTN were changed from Muscular dystrophy, limb-girdle, type 2J 608807 to Muscular dystrophy, limb-girdle, type 2J, 608807; Limb girdle muscular dystrophy; Distal myopathy; Myofibrillar myopathy; Congenital myopathy; dilated cardiomyopathy

30 Apr 2019, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: TTN were set to 26392295; 12145747

30 Apr 2019, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to TTN.

30 Apr 2019, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source South West GLH was added to TTN.

27 Jul 2016, Gel status: 1

panel promoted to version 1

Sarah Leigh (Genomics England Curator)

Comments from Fiona Karet included. A Green review for each gene relevant for this panel on the Gene Advisor download has been included.

26 Jul 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).

26 Jul 2016, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for TTN were set to Muscular dystrophy, limb-girdle, type 2J 608807

26 Jul 2016, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for TTN were set to Tibial muscular dystrophy, tardive, 600334

14 Jun 2016, Gel status: 2

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

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

9 Jun 2016, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for TTN were set to Cardiomyopathy, dilated, 1G, 604145; Cardiomyopathy, familial hypertrophic, 9, 613765; Muscular dystrophy, limb-girdle, type 2J 608807; Myopathy, early-onset, with fatal cardiomyopathy, 611705; Myopathy, proximal, with early respiratory muscle involvement, 603689; Tibial muscular dystrophy, tardive, 600334

9 Jun 2016, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for TTN were set to 26392295; 12145747

29 May 2016, Gel status: 2

Gene classified by Genomics England curator

Ellen Thomas (Genomics England Curator)

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

28 Jul 2015, Gel status: 3

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene TTN was changed to BIALLELIC, autosomal or pseudoautosomal

28 Jul 2015, Gel status: 3

Added New Source

Ellen McDonagh (Genomics England Curator)

TTN was added to Limb girdle muscular dystrophypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen

28 Jul 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene TTN was changed to BIALLELIC, autosomal or pseudoautosomal

28 Jul 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

TTN was added to Limb girdle muscular dystrophypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen

28 Jul 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

TTN was added to Limb girdle muscular dystrophypanel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen