ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.93166C>T (p.Arg31056Ter) (rs72648250)

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Total submissions: 6
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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 RCV000209605 SCV000189705 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 RCV000578520 SCV000680710 pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing The R28488X pathogenic variant in the TTN gene has been reported previously, using alternative nomenclature, to segregate with dilated cardiomyopathy in multiple affected individuals in a single family (Herman et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R28488X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is located in the A-band of the titin protein, where the majority of pathogenic truncating variants have been reported.
Ambry Genetics RCV000619547 SCV000735415 pathogenic Cardiovascular phenotype 2019-04-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Invitae RCV000705561 SCV000834562 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-10-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg31056*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with dilated cardiomyopathy in a family (PMID: 22335739) and has been observed in several individuals with dilated cardiomyopathy (PMID: 22335739, 28045975). This variant is also known as p.R29415* in the literature. ClinVar contains an entry for this variant (Variation ID: 223326). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected 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 Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000578520 SCV000856943 likely pathogenic not provided 2017-09-19 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845449 SCV000987534 pathogenic Familial dilated cardiomyopathy criteria provided, single submitter clinical testing

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