Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000700102 | SCV000828843 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-09-29 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg18554*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 577369). 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. |
| Ai |
RCV002223920 | SCV002502834 | likely pathogenic | not provided | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002440503 | SCV002752699 | likely pathogenic | Cardiovascular phenotype | 2022-03-18 | criteria provided, single submitter | clinical testing | The p.R9489* variant (also known as c.28465C>T), located in coding exon 114 of the TTN gene, results from a C to T substitution at nucleotide position 28465. This changes the amino acid from an arginine to a stop codon within coding exon 114. 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 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, |
RCV002477607 | SCV002799027 | 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 | 2021-10-10 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV003227836 | SCV003925251 | likely pathogenic | Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9 | 2022-08-03 | criteria provided, single submitter | clinical testing | The c.55660C>T p.(Arg18554Ter) variant in the TTN gene has previously been deposited in ClinVar [ClinVar ID: 577369] as Likely Pathogenic and to our current knowledge has not been reported in affected individuals in the literature. The c.55660C>T variant is observed in 2 alleles (~0.0006%minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.55660C>T variant in TTN is located in exon 287 of this 363-exon gene, predicted to incorporate a premature termination codon (p.(Arg18554Ter), and is expected to result in loss-of-function either through protein truncation or nonsense-mediated mRNA decay. The p.(Arg18554Ter) residue is within the A-band of TTN, where most variants associated with dilated cardiomyopathy are located [PMID:26777568, 27869827,28045975]. Individuals with pathogenic truncating variants in TTN also have a high prevalence of atrial and ventricular arrhythmias [PMID:32964742; 30333491]. Based on available evidence, this c.55660C>T p.(Arg18554Ter) variant identified in the TTN gene is classified as Likely Pathogenic. |
| Institute of Human Genetics, |
RCV003237351 | SCV003936052 | likely pathogenic | Dilated cardiomyopathy 1G | 2023-04-28 | criteria provided, single submitter | clinical testing |