Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152488 | SCV000201629 | uncertain significance | not specified | 2014-04-03 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The Phe2878fs v ariant in TTN has not been reported in individuals with cardiomyopathy. Data fro m large population studies is insufficient to assess the frequency of this varia nt. This frameshift variant is predicted to alter the protein?s amino acid seque nce beginning at position 2878 and lead to a premature termination codon 10 amin o acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly ass ociated with DCM and the majority occur in exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), while this variant occurs in the I-band . Although the data support that the Phe2878fs variant may be pathogenic, additi onal studies are needed to fully assess its clinical significance. |
| Labcorp Genetics |
RCV005222776 | SCV005861782 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-09-09 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Phe2878Trpfs*10) 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 not present in population databases (gnomAD no frequency). 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 clinical features of autosomal dominant TTN-related conditions (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 166303). 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. |