Submissions for variant NM_001267550.2(TTN):c.29042-2A>C

gnomAD frequency: 0.00060  dbSNP: rs6716782

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209530	SCV000189753	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in three individuals in this cohort and is located in an exon with intermediate levels of cardiac expression. 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.
GeneDx	RCV000725218	SCV000236819	likely benign	not provided	2020-11-04	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy and arrhythmia (Roberts et al., 2015; Choi et al., 2018); however, detailed clinical information and segregation data were not provided; Canonical splice site variant with an unclear effect on protein function; Not located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 25589632, 26777568, 22335739, 30535219)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000184197	SCV000272615	uncertain significance	not specified	2016-03-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.25310-2A>C va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.2% (12/6990) of African chromosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs6716782). This variant occurs in the invariant region (+/- 1,2) o f the splice consensus sequence and is predicted to alter splicing. However, how this variant will impact the protein is unknown. In summary, while the clinical significance of the c.25310-2A>C variant is uncertain, its frequency suggests t hat it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000725218	SCV000335087	uncertain significance	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Invitae	RCV001084964	SCV000542375	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852882	SCV000995616	likely benign	Cardiomyopathy	2019-05-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000852882	SCV001333228	likely benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001336905	SCV001530424	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2018-10-16	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000725218	SCV003819837	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907642	SCV004724996	likely benign	TTN-related condition	2023-07-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209530	SCV000189635	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	flagged submission	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with intermediate levels of cardiac expression. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000725218	SCV001742766	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000725218	SCV001919415	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725218	SCV001966374	uncertain significance	not provided		no assertion criteria provided	clinical testing