ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.325C>T (p.Arg109Ter) (rs150954246)

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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 RCV000209360 SCV000189797 uncertain significance 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 RCV000578708 SCV000680822 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTN gene. The R109X variant has not been published as pathogenic or been reported as benign to our knowledge. R109X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Additionally, other nonsense variants in the TTN gene have been reported in HGMD in association with dilated cardiomyopathy (Stenson et al., 2014). However, truncating TTN variants have been reported in approximately 3% of control alleles, and the R109X variant is not located in the A-band region of TTN, where the majority of truncating variants associated with DCM have been reported (Herman et al., 2010). Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Illumina Clinical Services Laboratory,Illumina RCV000779292 SCV000915874 uncertain significance TTN-Related Disorders 2018-12-05 criteria provided, single submitter clinical testing The TTN c.325C>T (p.Arg109Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg109Ter variant has been reported in one study in which it was noted to be present in a publicly available control population (Roberts et al. 2015). The variant has not been reported in association with disease. The p.Arg109Ter variant is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project though this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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