Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000642743 | SCV000764430 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-08-16 | criteria provided, single submitter | clinical testing | 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. 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). ClinVar contains an entry for this variant (Variation ID: 534995). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (rs753333359, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg17915*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
| Ambry Genetics | RCV002458069 | SCV002739442 | pathogenic | Cardiovascular phenotype | 2021-03-16 | criteria provided, single submitter | clinical testing | The p.R8850* pathogenic mutation (also known as c.26548C>T), located in coding exon 106 of the TTN gene, results from a C to T substitution at nucleotide position 26548. This changes the amino acid from an arginine to a stop codon within coding exon 106. 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). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TTN-related disease (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Institute of Medical Genetics and Applied Genomics, |
RCV002464279 | SCV002759350 | pathogenic | Early-onset myopathy with fatal cardiomyopathy | 2022-12-07 | criteria provided, single submitter | clinical testing |