Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000512814 | SCV000609007 | likely pathogenic | not provided | 2017-05-01 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000826188 | SCV000967732 | likely pathogenic | Primary dilated cardiomyopathy | 2017-06-09 | criteria provided, single submitter | clinical testing | The p. Pro4115GlnfsX14 (NM_133432.3 c.12344delC) variant in TTN has not been pre viously reported in individuals with dilated cardiomyopathy (DCM). It has been i dentified in 1/111050 European chromosomes by the genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a f rameshift, which alters the protein?s amino acid sequence beginning at position 4115 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshif t and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). Th e p. Pro4115GlnfsX14 variant is located in the I-band in the highly expressed ex on 49. In summary, although additional studies are required to fully establish i ts clinical significance, this variant is likely pathogenic. |
| Labcorp Genetics |
RCV001223187 | SCV001395324 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2025-01-20 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Pro4353Glnfs*14) 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 (no rsID available, gnomAD 0.0009%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with personal or family history of dilated cardiomyopathy (PMID: 37279760); however, the role of the variant in this condition is currently unclear. This variant is also known as c.12344delC (p.Pro4115Glnfs*14). ClinVar contains an entry for this variant (Variation ID: 444542). 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, 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, 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. |