Submissions for variant NM_001267550.2(TTN):c.81262_81269del (p.Gln27088fs)

dbSNP: rs869312059

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209362	SCV000189664	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in two individuals in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	RCV000209362	SCV000845658	likely pathogenic	Primary dilated cardiomyopathy	2017-09-07	criteria provided, single submitter	clinical testing	This frameshift variant has not been detected in large population studies (ExAC database), but has been found in two patients from an internal research DCM cohort (ClinVar variation ID: 223293) . The TTN protein has a critical role in the mechanical properties of cardiac muscle cells. Truncating variants in TTN are a known major cause of DCM (15-20% of cases), and although 1-3% of healthy individuals have truncating TTN variants (Herman et al. 2012 N Engl J Med.366(7):61928) these variants are more likely to reside in TTN isoforms with lower functional expression in cardiac tissue. Pathogenic TTN truncating variants have been shown to cluster in exons with a functional expression above 90% (Roberts et al. 2015 Sci Transl Med. 7(270):270ra6). The c.81262_81269del variant occurs in an exon which is expressed in 100% of TTN cardiac isoforms (Roberts et al. (2015)) and is therefore likely to be pathogenic. This variant has been detected in another affected family member.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379495	SCV001577307	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2020-09-22	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 223293). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Gln27088Cysfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.