Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523157 | SCV000620907 | likely pathogenic | not provided | 2017-09-15 | criteria provided, single submitter | clinical testing | The c.55979delG variant in the TTN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.55979delG variant causes a frameshift starting with codon Serine 18660, changes this amino acid to a Isoleucine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Ser18660IlefsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.55979delG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.55979delG as a likely pathogenic variant. |
| Ambry Genetics | RCV002456016 | SCV002614807 | likely pathogenic | Cardiovascular phenotype | 2018-04-17 | criteria provided, single submitter | clinical testing | The c.33707delG variant, located in coding exon 131 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 33707, causing a translational frameshift with a predicted alternate stop codon (p.S11236Ifs*3). 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%). 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. As such, this alteration is classified as likely pathogenic. |