ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.29042-2A>C (rs6716782)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209530 SCV000189635 likely pathogenic 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 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.
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 RCV000184197 SCV000236819 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing The c.28091-2 A>C variant (reported as c.29042-2 A>C due to the use of an alternate transcript) has previously been reported in one individual with a clinical diagnosis of DCM and in three individuals for whom clinical information was not provided (Roberts et al., 2015). Additionally, this variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000272615.1; Landrum et al., 2016). The c.28091-2 A>C variant destroys the canonical splice acceptor site in intron 98 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, c.28091-2 A>C is 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). Moreover, the NHLBI Exome Sequencing Project and the 1000 Genomes project report c.28091-2 A>C was observed in 6/3722 (0.2%) alleles from individuals of African American ancestry and in 1/1322 (0.1%) alleles from individuals of African background, respectively, indicating it may be a rare benign variant in these populations. Finally, data from the Exome Aggregation Consortium (ExAC) includes one individual who is homozygous for this variant. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Laboratory for Molecular Medicine,Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725218 SCV000335087 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
Invitae RCV001084964 SCV000542375 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-12-04 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 uncertain significance Cardiomyopathy 2018-01-02 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].

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.