ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.40558+1G>A (rs368219776)

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Total submissions: 10
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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 2019-01-18 criteria provided, single submitter clinical testing 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 identified in 4/15632 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368219776). The c.32854+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice and other truncating variants in TTN are strongly associated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014). Variants in the I-band, where the c.32854+1G>A variant 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 for a pathogenic role, the clinical significance of the c.32854+1G>A variant is uncertain.
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 2020-10-06 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. 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.
Illumina Clinical Services Laboratory,Illumina RCV001132686 SCV001292354 benign Myopathy, myofibrillar, 9, with early respiratory failure 2019-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001132687 SCV001292355 benign Tibial muscular dystrophy 2019-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725594 SCV001747285 uncertain significance not provided 2021-05-01 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477783 SCV000536714 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Tibial muscular dystrophy; 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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