Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000541321 | SCV000642478 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-29 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp29755*) 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 0.01%). This premature translational stop signal has been observed in individuals with clinical features of dilated cardiomyopathy or atrial fibrillation (PMID: 30535219; Invitae). ClinVar contains an entry for this variant (Variation ID: 466669). 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. |
| Ambry Genetics | RCV002367859 | SCV002659367 | likely pathogenic | Cardiovascular phenotype | 2023-07-12 | criteria provided, single submitter | clinical testing | The p.W20690* variant (also known as c.62070G>A), located in coding exon 161 of the TTN gene, results from a G to A substitution at nucleotide position 62070. This changes the amino acid from a tryptophan to a stop codon within coding exon 161. 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 (referred to as p.Trp29755*, c.89265G>A) has been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA, 2018 12;320:2354-2364). In addition to the clinical data presented in the literature, 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, |
RCV002497135 | SCV002810500 | 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 | 2021-09-20 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003114664 | SCV003798744 | uncertain significance | not provided | 2023-01-27 | criteria provided, single submitter | clinical testing | Reported in a cohort of individuals with early onset atrial fibrillation; however, segregation data and additional clinical information was not included (Yoneda et al., 2021); 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; This variant is associated with the following publications: (PMID: 30535219, 34495297) |