ClinVar Miner

Submissions for variant NM_133378.4(TTN):c.10361-1G>A (rs869312099)

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Total submissions: 4
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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 RCV000209734 SCV000189749 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000296352 SCV000340883 uncertain significance not provided 2016-03-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000680134 SCV000807578 pathogenic 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 2017-09-01 criteria provided, single submitter clinical testing This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory with a missense variant (I7241V - phase unknown) in a newborn male with hypotonia, minimal movements, arthrogyposis multiplex, mild asymmetry of olfactory bulbs, PFO, femur fractures, family history of a sister with a similar phenotype (not tested)
Invitae RCV000794667 SCV000934088 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-10-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 48 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 223347). 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.

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