Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000620544 | SCV000737285 | uncertain significance | Cardiovascular phenotype | 2017-06-21 | criteria provided, single submitter | clinical testing | The c.5322_5328delGAGAATGinsAGT variant, located in coding exon 26 of the TTN gene, results from the deletion of 7 nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.R1775Vfs*10). This exon is located in the near Z-disk/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%). While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med. 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet. 2017 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV005001088 | SCV005626417 | uncertain significance | not provided | 2024-07-11 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease |