Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Cardiovascular Biomedical Research Unit, |
RCV000208933 | SCV000189639 | 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 with low levels of cardiac expression. 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. |
| Invitae | RCV001308459 | SCV001497910 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-09-15 | criteria provided, single submitter | clinical testing | This variant is also known as c.33643+1G>A. ClinVar contains an entry for this variant (Variation ID: 223272). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632). This sequence change affects a donor splice site in intron 139 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs746588865, gnomAD 0.003%). |
| Fulgent Genetics, |
RCV002485366 | SCV002788804 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 | 2021-09-09 | criteria provided, single submitter | clinical testing | |
| Athena Diagnostics | RCV003482243 | SCV004229382 | uncertain significance | not provided | 2023-01-13 | criteria provided, single submitter | clinical testing | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant is expected to impact normal RNA splicing. However, this variant is predicted to maintain the reading frame of the transcript. The clinical relevance of such a change in this region of the gene has not been established and the effect on protein function is uncertain. This variant occurs in the I-band of the TTN gene and affects a canonical splice site in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). |