ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.54112del (p.Glu18038fs) (rs794729325)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184313 SCV000236938 pathogenic not provided 2014-02-12 criteria provided, single submitter clinical testing c.49189delG: p.Glu16397ArgfsX47 (E16397RfsX47) in exon 230 of the TTN gene (NM_001256850.1). The normal sequence with the base that is deleted in braces is: CCGG{G}AGGA. Although the c.49189delG mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glutamic acid 16397, changing it to an Arginine, and creating a premature stop codon at position 47 of the new reading frame, denoted p.Glu16397ArgfsX47. 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.49189delG 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.49189delG in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s).
Invitae RCV000476691 SCV000542980 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-05-01 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 280 of the TTN mRNA (c.54112delG), causing a frameshift at codon 18038. This creates a premature translational stop signal (p.Arg17577Serfs*3) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000620137 SCV000737107 likely pathogenic Cardiovascular phenotype 2016-07-14 criteria provided, single submitter clinical testing The c.26917delG variant, located in coding exon 107 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 26917, causing a translational frameshift with a predicted alternate stop codon (p.E8973Rfs*47). This alteration is located in the A-band region of the N2-B isoform of the titin protein. This variant was previously reported in the SNPDatabase as rs794729325, but was absent from population-based cohorts in the Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project databases. Truncating alterations in TTN were observed at a significantly higher frequency among patients with dilated cardiomyopathy (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). The functional mechanism of TTN truncations leading to DCM is not well understood; however, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this variant is classified as likely pathogenic.

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