ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter) (rs574660186)

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Total submissions: 7
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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 RCV000157564 SCV000189693 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 RCV000157564 SCV000207310 likely pathogenic Primary dilated cardiomyopathy 2015-05-06 criteria provided, single submitter clinical testing
GeneDx RCV000255593 SCV000322336 pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing The R20858X pathogenic variant in the TTN gene has been reported previously in one individual with DCM (Herman et al., 2012). Additionally, the R20858X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles; however, R20858X 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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255593 SCV000338691 likely pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing
Invitae RCV000684782 SCV000642456 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 22499 (p.Arg22499*) of the TTN gene. It is expected to result in a disrupted protein product. 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 and are considered to be pathogenic for the disease (PMID: 25589632). This particular variant has been observed in several individuals with dilated cardiomyopathy (PMID: 22335739, 25589632). ClinVar contains an entry for this variant (Variation ID: 180573). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000680139 SCV000807583 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Distal myopathy Markesbery-Griggs type; Hereditary myopathy with early respiratory failure; Myopathy, early-onset, with fatal cardiomyopathy; Familial hypertrophic cardiomyopathy 9 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory: heterozygous (maternally inherited) in a 12-year-old female with dilated cardiomyopathy and paternal family history of dilated cardiomyopathy (who also carried a paternally inherited likely pathogenic variant in BAG3); in trans with a missense variant in a 14-year-old female with global delays, epilepsy, scoliosis, clubbed digits, constipation (who also carried a de novo pathogenic variant in KCNT1).
Blueprint Genetics RCV000255593 SCV000928048 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing

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