ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.48015_48016del (p.Asp16007fs) (rs794729319)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184306 SCV000236931 pathogenic not provided 2014-04-16 criteria provided, single submitter clinical testing c.43092_43093delAG: p.Asp14366ProfsX19 (D14366PfsX19) in exon 206 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces is: AAAC{AG}GGGA. Although the c.43092_43093delAG 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 14366, changing it to a Proline, and creating a premature stop codon at position 19 of the new reading frame, denoted p.Asp14366ProfsX19. 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.43092_43093delAG 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.43092_43093delAG in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics RCV000618133 SCV000737249 likely pathogenic Cardiovascular phenotype 2018-11-06 criteria provided, single submitter clinical testing The c.20820_20821delAG variant, located in coding exon 83 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 20820 to 20821, causing a translational frameshift with a predicted alternate stop codon (p.D6942Pfs*19). 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.

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