Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000040399 | SCV000064090 | uncertain significance | not specified | 2019-05-10 | criteria provided, single submitter | clinical testing | The c.50143+1G>A variant in TTN has been identified in 1 individual with DCM (LMM data). It has also been identified in 0.05% (34/72786) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, the sequencing quality of this region was low. This variant occurs in the invariant region (+/- 1, 2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice site variants and other truncating variants in TTN are associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014), where this variant is located, and/or are located in an exon that is highly expressed in the heart (Roberts 2015). In summary, the clinical significance of the c.50143+1G>A variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate. |
| CHEO Genetics Diagnostic Laboratory, |
RCV001798166 | SCV002042556 | uncertain significance | Cardiomyopathy | 2019-08-08 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002444494 | SCV002753698 | uncertain significance | Cardiovascular phenotype | 2022-11-21 | criteria provided, single submitter | clinical testing | The c.30652+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 122 of the TTN gene. Coding exon 122 is located in the A-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 variant (referred to as c.50143+1G>A) has been detected in an individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). 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 and may result in the creation or strengthening of a novel 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. |