Submissions for variant NM_001267550.2(TTN):c.60931C>T (p.Arg20311Ter)

dbSNP: rs869312055

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209305	SCV000189658	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.
Revvity Omics, Revvity	RCV001781627	SCV002021520	likely pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798695	SCV002042575	likely pathogenic	Cardiomyopathy	2020-02-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853335	SCV002300223	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg20311*) 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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 25589632, 31317183, 31983221, 32880476). This variant is also known as c.33736C>T (p.Arg11246*). ClinVar contains an entry for this variant (Variation ID: 223288). 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). 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.
Ambry Genetics	RCV002453753	SCV002614410	likely pathogenic	Cardiovascular phenotype	2024-06-13	criteria provided, single submitter	clinical testing	The p.R11246* variant (also known as c.33736C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 33736. This changes the amino acid from an arginine to a stop codon within coding exon 131. 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.Arg20311X, c.60931C>T) has been detected in dilated cardiomyopathy (DCM) cohorts (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 Mar;21:326-336). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic.
Center for Human Genetics, University of Leuven	RCV000209305	SCV002817395	likely pathogenic	Primary dilated cardiomyopathy	2022-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001781627	SCV005079486	likely pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	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 (PMID: 22335739); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31317183, 31983221, 22335739, 25589632, 29377983, 32880476)