Submissions for variant NM_001267550.2(TTN):c.63601C>T (p.Arg21201Ter)

dbSNP: rs764243269

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209814	SCV000189691	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.
Invitae	RCV001239700	SCV001412593	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg21201*) 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 (rs764243269, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with autosomal dominant and autosomal recessive TTN-related conditions (PMID: 22335739, 33449170, 33874732; Invitae). This variant is also known as c.58678C>T (p.Arg19560X). ClinVar contains an entry for this variant (Variation ID: 223314). 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.
GeneDx	RCV000786239	SCV001773394	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	Observed with a missense variant on the opposite allele (in trans) in patients with a congenital myopathy, including two individuals with childhood-onset cardiomyopathy (Dai et al., 2015; Rees et al., 2021; Wacker et al., 2023); 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: 24980681, 22335739, 33874732, 34540771, 25987458, 25589632, 33449170, 26735901, 37345726)
Revvity Omics, Revvity	RCV000786239	SCV002021488	likely pathogenic	not provided	2021-02-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798696	SCV002042592	likely pathogenic	Cardiomyopathy	2021-01-15	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV002057055	SCV002495737	likely pathogenic	Left ventricular noncompaction cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002453754	SCV002613752	likely pathogenic	Cardiovascular phenotype	2022-07-06	criteria provided, single submitter	clinical testing	The p.R12136* variant (also known as c.36406C>T), located in coding exon 133 of the TTN gene, results from a C to T substitution at nucleotide position 36406. This changes the amino acid from an arginine to a stop codon within coding exon 133. 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.Arg19560X (c.58678C>T), p.R21201* (c.63601C>T), and 2:179452435G>A) has been detected in individuals reported to have dilated, peripartum or left ventricular noncompaction cardiomyopathies (Herman DS et al. N Engl J Med, 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Ware JS et al. N Engl J Med, 2016 Jan;374:233-41; Schultze-Berndt A et al. Front Pediatr, 2021 Sep;9:722926), and has also been detected in an individual from a myopathy cohort who also had a TTN missense variant (Dai Y et al. Neuromuscul Disord, 2015 Aug;25:617-24). 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). As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503827	SCV002801886	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2022-03-09	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786239	SCV000924981	likely pathogenic	not provided	2016-12-16	no assertion criteria provided	provider interpretation	GeneDx classifies this variant as pathogenic. Given the type of variant and its location within the gene, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature and is not listed in ClinVar. Truncation Variants in TTN The presence of truncating TTN variants in controls indicates that not all such variants can be presumed pathogenic or, if disease-causing, may not be the sole contributor to disease in a family. TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls (indicating that not all such variants are disease-causing). While truncating variants in TTN have been associated with disease, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al. 2012). In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families—pointing to the difficulty in determining variant pathogenicity for a specific truncating variant. Norton et al., identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Cardiodb.org Data Roberts et al, 2015 performed cardiac phenotyping of 5267 affected and unaffected individuals as well as TTN DNA sequencing and RNA and protein analyses heart tissue. They have a resource at cardiodb.org/titin that lists the relative inclusion of TTN exons in different isoforms and provides information to guide assessment of pathogenicity of specific truncation variants in the gene. Variants located in the A-band and present in cardiac isoforms of the protein were enriched in DCM patients versus controls. The genomic coordinates for this variant are chr2:179452435G>A. LRG exon number is 257, N2BA transcript is 206. It is located in the A-band, 100% spliced-in in DCM patients and 86% of a GTEx population. Population Data The variant was reported online in 1 of 59,791 individuals in the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 unrelated individuals of African, Asian, European, and Latino descent. Specifically, the variant was observed in 1 of 8,187 individuals of South Asian descent (0.006% MAF). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was reported online in 2 of 125,417 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. This dataset includes the ExAC dataset, but is still in beta mode. Specifically, the variant was observed in 1 of 15,429 individuals of South Asian descent (0.0003% MAF) and 1 of 17,808 people of Latino descent.