ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.41473C>T (p.Arg13825Ter) (rs869312043)

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Total submissions: 3
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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 RCV000209073 SCV000189642 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 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 RCV000593559 SCV000704201 uncertain significance not provided 2016-12-08 criteria provided, single submitter clinical testing
Invitae RCV000552893 SCV000643141 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-06-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg13825*) in the TTN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 25589632, Invitae). ClinVar contains an entry for this variant (Variation ID: 223274). This variant identified in the TTN gene is located in the I band of the resulting protein (PMID: 25589632). In summary, although this is a rare truncating variant, truncating variants in this region of the TTN gene have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating mutations in this region have also been reported to cause autosomal recessive congenital myopathy (PMID: 23975875). Therefore without additional functional and/or genetic data, this variant has been classified as a Variant of Uncertain Significance.

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