Submissions for variant NM_001267550.2(TTN):c.85008_85011del (p.Glu28338fs)

dbSNP: rs869312100

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	RCV000209304	SCV000189759	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual 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.
Invitae	RCV001242255	SCV001415328	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu28338Hisfs*9) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive distal titinopathy (PMID: 26627873, 27796757). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 223352). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002282042	SCV002571257	likely pathogenic	not provided	2022-03-04	criteria provided, single submitter	clinical testing	Located in the A-band region of titin, in which the majority of loss of function variants have been associated with autosomal dominant TTN-related titinopathies (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with dilated cardiomyopathy in the published literature (Li et al., 2021); This variant is associated with the following publications: (PMID: 26627873, 25589632, 22335739, 27796757, 33941202)