Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000040543 | SCV000064234 | likely pathogenic | Primary dilated cardiomyopathy | 2012-02-06 | criteria provided, single submitter | clinical testing | The Asn20586fs variant (TTN) has not been reported in the literature nor previou sly identified by our laboratory. This variant is predicted to cause a frameshif t, which alters the protein's amino acid sequence beginning at codon 20586 and l eads to a premature stop codon 14 amino acids downstream. This alteration is the n predicted to lead to a truncated or absent protein (loss-of-function). Loss-of -function variants in TTN are common in patients with DCM (Jon Seidman, pers. co mm.). Therefore, the Asn20586fs variant is likely to be pathogenic, though segre gation studies and functional analyses are required to fully establish the patho genicity of this variant. |
Ambry Genetics | RCV002326748 | SCV002630359 | likely pathogenic | Cardiovascular phenotype | 2020-08-04 | criteria provided, single submitter | clinical testing | The c.42263_42266dupAGAA variant, located in coding exon 152 of the TTN gene, results from a duplication of AGAA at nucleotide position 42263, causing a translational frameshift with a predicted alternate stop codon (p.N14089Kfs*14). This alteration was reported in one 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 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 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. |