ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.93166C>T (p.Arg31056Ter) (rs72648250)

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
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209605 SCV000189705 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.
GeneDx RCV000578520 SCV000680710 pathogenic not provided 2021-04-23 criteria provided, single submitter clinical testing Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 223326; Landrum et al., 2016); 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: 25589632, 23975875, 22335739, 24119082, 31317183, 31514951)
Ambry Genetics RCV000619547 SCV000735415 pathogenic Cardiovascular phenotype 2019-04-10 criteria provided, single submitter clinical testing The p.R21991* pathogenic mutation (also known as c.65971C>T), located in coding exon 166 of the TTN gene, results from a C to T substitution at nucleotide position 65971. This changes the amino acid from an arginine to a stop codon within coding exon 166. This variant 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 truncating alteration has been reported in unrelated individuals with dilated cardiomyopathy (DCM) and has been reported to segregate with disease in families (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Franaszczyk M. PLoS ONE. 2017;12(1):e0169007). 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.
Invitae RCV000705561 SCV000834562 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-08-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg31056*). 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 to segregate with dilated cardiomyopathy in a family (PMID: 22335739) and has been observed in several individuals with dilated cardiomyopathy (PMID: 22335739, 28045975). This variant is also known as p.R29415* in the literature. ClinVar contains an entry for this variant (Variation ID: 223326). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000578520 SCV000856943 likely pathogenic not provided 2017-09-19 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845449 SCV000987534 pathogenic Primary familial dilated cardiomyopathy criteria provided, single submitter 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.