ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.51436+1G>A

gnomAD frequency: 0.00001  dbSNP: rs761807131
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184231 SCV000236853 likely pathogenic not provided 2023-10-06 criteria provided, single submitter clinical testing Has been reported in association with DCM (Klauke et al., 2017; Bourfiss et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); 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); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28135719, 31785789, 22335739, 29253866, 36264615)
Labcorp Genetics (formerly Invitae), Labcorp RCV000538838 SCV000642435 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 271 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs761807131, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy (PMID: 29253866; Invitae). ClinVar contains an entry for this variant (Variation ID: 202384). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, University of Leuven RCV003237342 SCV002817389 uncertain significance Primary dilated cardiomyopathy 2022-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV003165413 SCV003858762 uncertain significance Cardiovascular phenotype 2023-03-07 criteria provided, single submitter clinical testing The c.24241+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 98 of the TTN gene. Exon 98 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 (also referred to as c.51436+1G>A and 2:179474816C>T) has been detected in an individual with dilated cardiomyopathy and in an individual from a developmental disorders cohort (Klauke B et al. PLoS One, 2017 Dec;12:e0189489; McRae JF et al. Nature, 2017 Feb;542:433-438). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV000184231 SCV004238388 pathogenic not provided 2023-03-06 criteria provided, single submitter clinical testing
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen RCV000491861 SCV000298126 likely pathogenic Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided 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.