Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000592248 | SCV000706652 | uncertain significance | not provided | 2017-02-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002395529 | SCV002701793 | uncertain significance | Cardiovascular phenotype | 2022-01-03 | criteria provided, single submitter | clinical testing | The c.14134+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 52 in the TTN gene. Exon 52 is located in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003767387 | SCV004597305 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-06-22 | criteria provided, single submitter | clinical testing | 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. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 500622). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 225 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. |