ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.79684C>T (p.Arg26562Ter) (rs869025545)

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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 RCV000208201 SCV000189790 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.
Blueprint Genetics RCV000208201 SCV000264284 likely pathogenic Primary dilated cardiomyopathy 2015-10-09 criteria provided, single submitter clinical testing
Invitae RCV000476366 SCV000543063 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-09-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the TTN mRNA at codon 26562 (p.Arg26562*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the A-band of the TTN protein. This variant has been reported in the literature in individuals affected with unspecified cardiomyopathy or dilated cardiomyopathy (PMID: 25214167, 27886618). ClinVar contains an entry for this variant (Variation ID: 222861). This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Likely Pathogenic.

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