Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000216886 | SCV000271281 | likely pathogenic | Primary dilated cardiomyopathy | 2015-06-11 | criteria provided, single submitter | clinical testing | The p.Thr21710fs variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies, though the ability of these to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 21710 and leads to a premature termination codon 2 amino acids downstream. Thi s alteration is then predicted to lead to a truncated or absent protein. Framesh ift and other truncating variants in TTN are strongly associated with DCM if the y are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/ or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Thr21710fs variant is located in A-band in the highly expressed exon 275. In summary, although additional studies are required to fully establish its clin ical significance, the p.Thr21710fs variant is likely pathogenic. |
Ambry Genetics | RCV002338675 | SCV002636127 | likely pathogenic | Cardiovascular phenotype | 2021-03-18 | criteria provided, single submitter | clinical testing | The c.45637dupA variant, located in coding exon 153 of the TTN gene, results from a duplication of A at nucleotide position 45637, causing a translational frameshift with a predicted alternate stop codon (p.T15213Nfs*2). This exon 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 01;49:46-53). As such, this alteration is classified as likely pathogenic. |