ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.89896_89899ATTA[1] (p.Asn29967fs) (rs869312081)

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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 RCV000209065 SCV000189703 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.
GeneDx RCV000521895 SCV000617538 likely pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing The c.84977_84980delATTA likely pathogenic variant in the TTN gene has been reported in association with DCM (Herman et al., 2012); however, functional studies and segregation information were not provided. This variant causes a shift in reading frame starting at codon asparagine 28326, changing it to a methionine, and creating a premature stop codon at position 27 of the new reading frame, denoted p.Asn28326MetfsX27. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.84977_84980delATTA is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, the c.84977_84980delATTA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Blueprint Genetics RCV000521895 SCV000927539 likely pathogenic not provided 2018-02-20 criteria provided, single submitter clinical testing

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