Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000528221 | SCV000642767 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-11-04 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 12 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted 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 autosomal dominant dilated cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 466867). 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 Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, 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. |
| Laboratory for Molecular Medicine, |
RCV004017673 | SCV004847395 | uncertain significance | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | The c.1938+1G>T variant in TTN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 466867). This variant occurs within the canonical splice site (+1) and is predicted to cause altered splicing leading to an abnormal or absent protein. This variant is predicted to cause in-frame exon skipping of exon 12 (less than 10% of the protein), which has a 79% PSI. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting. |
| Ambry Genetics | RCV004992337 | SCV005521634 | uncertain significance | Cardiovascular phenotype | 2024-10-17 | criteria provided, single submitter | clinical testing | The c.1800+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 10 of the TTN gene. Coding exon 10 is located in the Z-disk region of the N2-B isoform of the titin protein and is not constitutively expressed in TTN transcripts (percent spliced in or PSI 79%). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. |