ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.12405del (p.Asn4135fs) (rs727503658)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152420 SCV000201459 likely pathogenic Primary dilated cardiomyopathy 2013-04-17 criteria provided, single submitter clinical testing The Asn3897fs variant in TTN has been identified by our laboratory in 1 Caucasia n individual with DCM (LMM unpublished data). Data from large population studies is insufficient to assess its frequency in the general population. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 3897 and lead to a premature termination codon 33 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM and the majority occur in the A-band (Herman 2012, LMM unpublished data). In su mmary, the predicted impact of this variant suggests that it is likely to be pat hogenic, but additional information is needed to fully establish its clinical si gnificance.
GeneDx RCV000184415 SCV000237040 uncertain significance not provided 2014-10-09 criteria provided, single submitter clinical testing c.11454delT: p.Asn3818LysfsX33 (N3818KfsX33) in exon 46 of the TTN gene (NM_001256850.1). The normal sequence with the base that is deleted in braces is: TCAA{T}GGCA. A variant of unknown significance has been identified in the TTN gene. The c.11454delT variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.11454delT variant causes a shift in reading frame starting at codon Asparagine 3818, changing it to a Lysine, and creating a premature stop codon at position 33 of the new reading frame, denoted p.Asn3818LysfsX33. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). Furthermore, c.11454delT is not 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). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics RCV000618476 SCV000736757 likely pathogenic Cardiovascular phenotype 2017-02-02 criteria provided, single submitter clinical testing The c.11316delT variant, located in coding exon 44 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 11316, causing a translational frameshift with a predicted alternate stop codon (p.N3772Kfs*33). This exon is located in the I-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.
Invitae RCV001299176 SCV001488255 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-10-15 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Asn4135Lysfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 166237). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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