ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.1800+1G>A

gnomAD frequency: 0.00005  dbSNP: rs397517497
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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039959 SCV000063650 likely pathogenic Primary dilated cardiomyopathy 2012-10-17 criteria provided, single submitter clinical testing The 1800+1G>A variant in TTN has not been reported in the literature but has bee n identified in a child with DCM previously tested by our laboratory (LMM unpubl ished data). This variant has not been identified by large and broad European Am erican and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS), which is consistent with a pathogenic role. However, we cannot exclude that it may be common in other populations. Th is variant occurs in the invariant region (+/- 1, 2) of the splice consensus seq uence and is predicted to cause altered splicing leading to an abnormal or absen t protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). In summary, this variant is likely pathogenic, though ad ditional studies are required to fully establish its clinical significance.
GeneDx RCV000184208 SCV000236830 uncertain significance not provided 2022-05-31 criteria provided, single submitter clinical testing Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Reported in an abstract, as a heterozygous variant in a child with high serum creatine kinase, mild motor weakness, mild sural hypertrophy, and muscle biopsy indicating a dystrophic process with reduced alpha-dystrophin staining, who also had a homozygous variant in the ISPD gene (Aksoy et al., 2019)
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000503453 SCV000588372 likely pathogenic Muscular dystrophy 2017-06-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000707086 SCV000836167 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-11-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 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 (rs397517497, gnomAD 0.05%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy and/or distal myopathy (PMID: 34553419, 34935411). ClinVar contains an entry for this variant (Variation ID: 46689). 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 Z band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). 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.

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.