Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000706544 | SCV000835601 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-07-10 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg17337*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with centronuclear myopathy and/or dilated cardiomyopathy (PMID: 25163546, 33449170; Invitae). This variant is also known as c.25390C>T (p.Arg8464*). ClinVar contains an entry for this variant (Variation ID: 582466). 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 | RCV002424719 | SCV002742680 | likely pathogenic | Cardiovascular phenotype | 2020-03-12 | criteria provided, single submitter | clinical testing | The p.R8272* variant (also known as c.24814C>T), located in coding exon 100 of the TTN gene, results from a C to T substitution at nucleotide position 24814. This changes the amino acid from an arginine to a stop codon within coding exon 100. 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. |