ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.107377+1G>A (rs112188483)

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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 RCV000209587 SCV000189713 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000413060 SCV000229482 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing
GeneDx RCV000413060 SCV000491354 likely pathogenic not provided 2016-12-21 criteria provided, single submitter clinical testing The c.99673+1 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor was it observed with any significant frequency in the 1000 Genomes Project. The c.99673+1 G>A variant is located in the M-line of titin, where the majority of truncating variants associated with muscular dystrophy have been reported. This variant destroys the canonical splice donor site in intron 310 and is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants have been reported in the TTN gene in association with TTN-related disorders (Stenson et al., 2014). The c.99673+1 G>A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Athena Diagnostics Inc RCV000413060 SCV000615984 pathogenic not provided 2016-09-06 criteria provided, single submitter clinical testing
Invitae RCV000797446 SCV000937003 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-10-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 361 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs112188483, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 28716623, 25214167). It has also been observed to segregate with disease in related individuals. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 196723). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473), but have not been definitively shown to cause cardiomyopathy (PMID: 25589632). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000413060 SCV001246030 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing

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