ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.82240C>T (p.Arg27414Ter)

gnomAD frequency: 0.00001  dbSNP: rs766840243
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184271 SCV000236894 pathogenic not provided 2019-08-19 criteria provided, single submitter clinical testing Has not been previously reported as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 31983221)
Invitae RCV001241231 SCV001414237 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-08-31 criteria provided, single submitter clinical testing 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. 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). ClinVar contains an entry for this variant (Variation ID: 202415). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 31251381, 31983221). This variant is present in population databases (rs766840243, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg27414*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics RCV002345648 SCV002650183 likely pathogenic Cardiovascular phenotype 2022-10-20 criteria provided, single submitter clinical testing The p.R18349* variant (also known as c.55045C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 55045. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 NM_001267550.2:c.82240C>T, p.Arg27414Ter) has been detected in an individual from a dilated cardiomyopathy cohort, and in an individual from a cohort without known cardiomyopathy; however, details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000184271 SCV002822734 likely pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing TTN: PVS1, PS4:Supporting
Department of Legal Medicine, University of Toyama RCV002305453 SCV002506988 pathogenic Third degree atrioventricular block 2022-05-06 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.