ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.101098delinsCT (p.Asp33700fs) (rs794729367)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184366 SCV000236991 pathogenic not provided 2014-07-30 criteria provided, single submitter clinical testing c.96175delinsCT: p.Asp32059LeufsX13 (D32059LfsX13) in exon 308 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces andinserted in brackets is: TAGT{G}[CT]ATGT. Although the c.96175delGinsCT mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Aspartic acid 32059, changing it to a Leucine, and creating a premature stop codon at position 13 of the new reading frame, denoted p.Asp32059LeufsX13. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.96175delGinsCT is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.96175delGinsCT in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM,DCM-CRDM panel(s).
Ambry Genetics RCV000617632 SCV000737160 likely pathogenic Cardiovascular phenotype 2016-09-07 criteria provided, single submitter clinical testing The c.73903delGinsCT variant, located in coding exon 185 of the TTN gene, results from the deletion of one nucleotide and insertion of two nucleotides, causing a translational frameshift with a predicted alternate stop codon (p.D24635Lfs*13). This variant is located in the M-band region of the N2-B isoform of the titin protein. This variant has not been reported in the literature to date; however, a similar frameshift alteration involving the same codon, p.D24635Vfs*13 (reported as c.101098_101099insT (p.Asp33700fs)), has been described in an individual with dilated cardiomyopathy (DCM) (Roberts AM et al. Sci Transl Med. 2015;7(270):270ra6). This c.73903delGinsCT variant was previously reported in the SNPDatabase as rs794729367, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6264 samples (12528 alleles) with coverage at this position. Truncating alterations in TTN have been observed at a significantly higher frequency among patients with DCM, or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3 of 231, 1%, P=3x10<sup>-16</sup>) and healthy controls (7 of 249, 3%, P=9x10<sup>-14</sup>). Among families with multiple relatives with DCM, studies also provided strong data demonstrating segregation of TTN truncations with disease (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TTN has not been clearly established as a mechanism of disease. As such, this variant is classified as likely pathogenic.

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