ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.16288C>T (p.Arg5430Ter) (rs772235481)

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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000312986 SCV000334048 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing
Invitae RCV000814903 SCV000955340 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-09-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg5430*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with early-onset atrial fibrillation (PMID: 30535219). ClinVar contains an entry for this variant (Variation ID: 282527). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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.
Athena Diagnostics Inc RCV000312986 SCV001880220 likely pathogenic not provided 2020-08-31 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity ( This variant has been identified in at least one individual with clinical features associated with this gene. This variant occurs in the I-band of the TTN gene, and is a nonsense variant in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). Nonsense and other truncating variants in TTN have been reported in patients with dominant cardiomyopathy, dominant tibial muscular dystrophy, recessive salih myopathy, recessive limb-girdle muscular dystrophy, and recessive centronuclear myopathy (OMIM# 188840). However, these types of variants have also been found in healthy individuals (PMID: 25589632). An alternative, in-frame, transcription start site has been identified between exons 239 and 240 (NM_001267550.1), suggesting that variants occurring in exons 1-239 may be rescued via transcription from the alternative site (PMID: 26473617). This variant falls within this region (exon 55). Cardiomyopathy and muscular dystrophy patients are reported to have truncating variants in the A-band and M-band of TTN, respectively, statistically more often than individuals in the general population (PMID: 25589632).
Baylor Genetics RCV000415222 SCV000328733 pathogenic Dilated cardiomyopathy 1G; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Familial hypertrophic cardiomyopathy 9 2015-07-04 no assertion criteria provided clinical testing Our laboratory reported two molecular diagnoses in NOTCH1 (NM_017617.3, c.6348C>G) and TTN (NM_133378.3, c.12556C>T)in one individual with reported features of delayed speech, dysmorphic features (hypertelorism with widened nasal bridge, over folded helices and prominent long philtrum), congenital heart disease (tricuspid valve dysplasia, sinus of valsalva dilatation and atrial enlargement), pulmonary lymphangiectasia, and transient neonatal cholestasis. The variant in NOTCH1 is predicted to cause a nonsense mutation and is categorized as deleterious by ACMGG guidelines [PMID: 18414213].

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.