ClinVar Miner

Submissions for variant NM_133378.4(TTN):c.32854+1G>A (rs368219776)

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Total submissions: 7
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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 RCV000209704 SCV000189731 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000221188 SCV000272642 uncertain significance not specified 2015-03-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The c.32854+1G> A variant in TTN has been reported in 1 individual with DCM, and segregated with disease in 1 affected relative (Herman 2012). This variant has also been identi fied in 4/15632 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368219776). The c.32854+1G>A variant occ urs in the invariant region (+/- 1,2) of the splice consensus sequence and is pr edicted to cause altered splicing leading to an abnormal or absent protein. Spli ce and other truncating variants in TTN are strongly associated with DCM, partic ularly if they are located in the exons encoding for the A-band region of the pr otein (Herman 2012, Pugh 2014). Variants in the I-band, where the c.32854+1G>A v ariant is located, occur at a greater frequency in controls than in individuals with DCM (Pugh 2014). This decreases the likelihood, but does not rule out that this variant has a role in disease. In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the c.32854+1G>A variant is un certain.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725594 SCV000338006 uncertain significance not provided 2018-06-11 criteria provided, single submitter clinical testing
Invitae RCV000456920 SCV000542903 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-12-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 219 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs368219776, ExAC 0.03%). This variant has been reported in the literature in individuals affected with a TTN-related disease (PMID: 22335739), but has also been reported in controls (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 223256). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770044 SCV000901470 uncertain significance Cardiomyopathy 2017-04-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778575 SCV000914879 uncertain significance TTN-Related Disorders 2019-01-12 criteria provided, single submitter clinical testing The TTN c.32854+1G>A variant (also referred to as c. 40558+1G>A or c. 35635+1G>A) occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in two studies and is found in two individuals with dilated cardiomyopathy; it is not clear if they are related (Herman et al. 2012). This variant was also present in a presumable healthy individual (Roberts et al. 2015) and it is reported at a frequency of 0.0002559 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the c.32854+1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477783 SCV000536714 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Distal myopathy Markesbery-Griggs type; Myopathy, myofibrillar, 9, with early respiratory failure; Myopathy, early-onset, with fatal cardiomyopathy; Familial hypertrophic cardiomyopathy 9 2015-11-13 no assertion criteria provided research

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