ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.88837A>T (p.Lys29613Ter)

gnomAD frequency: 0.00001  dbSNP: rs794729300
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
GeneDx RCV000184280 SCV000236903 pathogenic not provided 2022-09-06 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign in association with a TTN-related disorder to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; This variant is associated with the following publications: (PMID: 23975875, 25589632, 34135346)
Invitae RCV001049626 SCV001213685 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys29613*) 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 (rs794729300, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 202423). 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.
Ambry Genetics RCV002354499 SCV002660395 likely pathogenic Cardiovascular phenotype 2023-01-31 criteria provided, single submitter clinical testing The p.K20548* variant (also known as c.61642A>T), located in coding exon 159 of the TTN gene, results from an A to T substitution at nucleotide position 61642. This changes the amino acid from a lysine to a stop codon within coding exon 159. 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.88837A>T, p.Lys29613Ter) has been detected in an individual from a cohort without known cardiovascular disease; however, clinical details were limited (Lacaze P et al. NPJ Genom Med. 2021 Jun;6(1):51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Genetics and Molecular Pathology, SA Pathology RCV002466463 SCV002761367 likely pathogenic Dilated cardiomyopathy 1G 2022-02-07 criteria provided, single submitter clinical testing This variant is located in the TTN A-band which is a functional domain with a PSI of 100 (PVS1_Strong)

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.