ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.68885_68888dup (p.Ile22964fs) (rs757603460)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000489217 SCV000343026 likely pathogenic not provided 2016-07-15 criteria provided, single submitter clinical testing The c.61181_61184dupATAC TTN variant has not been reported in individuals with disease. The c.61181_61184dupATAC variant is located in the A-band region of the TTN protein.1 While truncating variants in this region have been reported in individuals in the general population, they have also been reported at a significantly higher frequency in individuals with dilated cardiomyopathy (DCM).1,2 Therefore, the c.61181_61184dupATAC TTN variant is classified as likely pathogenic. 1. Herman et al. N Engl J Med. 2012 Feb 16;366(7):619-28. 2. Pugh et al. Genet Med. 2014 Aug;16(8):601-8. AKT 7-15-16
Invitae RCV000469442 SCV000542438 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-09-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Ile22964Tyrfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs757603460, ExAC 0.009%). This variant has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 404732). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000489217 SCV000576689 pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing Although the c.63962_63965dupATAC pathogenic variant in the TTN gene has not been published to our knowledge, it is classified as a likely pathogenic variant in ClinVar by another clinical laboratory in association with DCM (ClinVar SCV000542438.1; Landrum et al., 2016). Of note, this laboratory denotes this variant as c.68885_68888dupATAC due to the use of an alternate transcript. The c.63962_63965dupATAC variant causes a shift in reading frame starting at codon Isoleucine 21323, changing it to a Tyrosine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Ile21323TyrfsX8. This pathogenic variant 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 et al., 2012). However, c.63962_63965dupATAC is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, this variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

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