Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000473644 | SCV000542599 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg25552*) 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 (rs545954490, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with clinical features of dilated cardiomyopathy (PMID: 30847666; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg22984*. ClinVar contains an entry for this variant (Variation ID: 404828). 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. |
| Blueprint Genetics | RCV000788867 | SCV000928139 | likely pathogenic | not provided | 2018-12-27 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002339116 | SCV002642580 | likely pathogenic | Cardiovascular phenotype | 2022-06-10 | criteria provided, single submitter | clinical testing | The p.R16487* variant (also known as c.49459C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 49459. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 NM_133378.4:c.68950C>T, p.Arg22984*) has been detected in a genetic testing cohort in an individual reported to have unspecified cardiomyopathy, and was also detected in a discovery cohort of biobank participants; however, details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Park J et al. Nat Med, 2021 01;27:66-72). 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, |
RCV002502607 | SCV002788228 | 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 | 2021-11-02 | criteria provided, single submitter | clinical testing |