ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.77145dup (p.Ser25716fs)

gnomAD frequency: 0.00001  dbSNP: rs1205409465
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801032 SCV000940784 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser25716Leufs*8) in the TTN gene. 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with early-onset atrial fibrillation (PMID: 30535219). ClinVar contains an entry for this variant (Variation ID: 646692). 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 RCV001008308 SCV001168076 likely pathogenic not provided 2022-12-02 criteria provided, single submitter clinical testing Identified in at least one patient with early onset atrial fibrillation in published literature (Choi et al., 2018; Yoneda et al., 2021); described as c.77145dupC due to the use of an alternate transcript; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 22335739, 30535219, 34495297)
Ambry Genetics RCV002336606 SCV002643552 likely pathogenic Cardiovascular phenotype 2023-10-24 criteria provided, single submitter clinical testing The c.49950dupC variant, located in coding exon 153 of the TTN gene, results from a duplication of C at nucleotide position 49950, causing a translational frameshift with a predicted alternate stop codon (p.S16651Lfs*8). 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%). This variant (referred to as c.77145dupC, p.Ser25716fs) has been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA, 2018 12;320:2354-2364). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 01;49:46-53). As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002495070 SCV002802016 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-07-16 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.