Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Cardiovascular Biomedical Research Unit, |
RCV000208995 | SCV000189717 | 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 intermediate 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. |
| Eurofins Ntd Llc |
RCV000376176 | SCV000339259 | uncertain significance | not provided | 2016-02-08 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002517420 | SCV002963479 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg7048*) in the TTN gene. 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 (rs770579313, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of limb girdle muscular dystrophy (PMID: 31618753). ClinVar contains an entry for this variant (Variation ID: 223333). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Pittsburgh Clinical Genomics Laboratory, |
RCV004783764 | SCV005397765 | uncertain significance | Myopathy, myofibrillar, 9, with early respiratory failure | 2024-04-12 | criteria provided, single submitter | clinical testing | This sequence variant is a single nucleotide substitution (C>T) at position 21142 of the coding sequence of the TTN gene that changes the codon at position 7048 from arginine to a premature termination codon. The Arg7048 residue falls in the I-band of the TTN-encoded titin protein (PMID: 25589632). RNA sequencing has found that the exon containing this variant is present in 25% of heart-derived mRNA sequencing reads (PMID: 25589632) and is nearly absent from muscle-derived mRNA (GTEx). This variant may not result in nonsense mediated decay, but it is expected to truncate the titin protein (PMID: 36685919). This is a previously reported variant (ClinVar 223333) that has been observed in an individual affected by limb-girdle muscular dystrophy (PMID: 31618753) as well as a healthy control (PMID: 25589632). This variant is present in 3 of 398592 alleles (0.0008%) in the gnomAD population dataset. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2 |