ClinVar Miner

Submissions for variant NM_001256850.1(TTN):c.28091-2A>C (rs6716782)

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Total submissions: 6
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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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725218 SCV000335087 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
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.
Invitae RCV000468293 SCV000542375 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-03-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 100 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. It is present within the part of the gene that encodes the I band. This variant is present in population databases (rs6716782, ExAC 0.2%). This variant has been reported in an individual included in a cohort of dilated cardiomyopathy cases, as well as in three individuals from a community-based control cohort without known cardiovascular disease (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 202355). Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant identified in the TTN gene is located in the I band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. In summary, this is a rare truncating variant in the I band and truncating variants in this region have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (PMID: 26701604, 22335739). As a result, this truncation is located outside of a clinically relevant region of the TTN gene (PMID: 25589632). In addition, because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. For these reasons, it has been classified as a Variant of Uncertain Significance.
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.

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