ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.79684C>T (p.Arg26562Ter)

dbSNP: rs869025545
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000208201 SCV000189790 likely pathogenic Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Blueprint Genetics RCV000208201 SCV000264284 likely pathogenic Primary dilated cardiomyopathy 2015-10-09 criteria provided, single submitter clinical testing
Invitae RCV000476366 SCV000543063 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-10-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg26562*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy or skeletal myopathy (PMID: 25589632, 27886618, 32039858). ClinVar contains an entry for this variant (Variation ID: 222861). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731523 SCV001983693 likely pathogenic Primary familial dilated cardiomyopathy 2021-09-28 criteria provided, single submitter clinical testing Variant summary: TTN c.71980C>T (p.Arg23994X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant is located in the A-band region, and in an exon that is highly expressed in the heart (Roberts_2015). The variant was absent in 248410 control chromosomes (gnomAD). c.71980C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Roberts_2015, Jansweijer_2017, Dalin_2017, Kolokotronis_2020) and was also found in patients affected with myopathies (Savarese_2014, Savarese_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV002336584 SCV002642495 pathogenic Cardiovascular phenotype 2021-09-30 criteria provided, single submitter clinical testing The p.R17497* pathogenic mutation (also known as c.52489C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 52489. 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 (also referred to as p.Arg26562*, c.79684C>T) has been detected in several individuals from dilated cardiomyopathy cohorts, and co-occurred with a second TTN nonsense variant in an individual with congenital myopathy; however, details were limited (Savarese M et al. Acta Neuropathol Commun, 2014 Sep;2:100; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Dalin MG et al. Int J Cardiol, 2017 Feb;228:742-748; Kolokotronis K et al. J Clin Med, 2020 Jul;9). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity Omics RCV003133177 SCV003815955 likely pathogenic not provided 2021-12-17 criteria provided, single submitter clinical testing
3billion RCV003152696 SCV003842133 pathogenic Dilated cardiomyopathy 1G 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000222861). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx RCV003133177 SCV004035663 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing Observed with additional TTN variants in individuals with skeletal myopathies, although it is not known if the variants were present on the same allele (in cis) or opposite alleles (in trans) in some cases (Savarese et al., 2014; Savarese et al., 2020a; Savarese et al., 2020b); 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; 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); This variant is associated with the following publications: (PMID: 25589632, 25214167, 32659924, 22335739, 32778822, 27886618, 34883393, 32039858)

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.