Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000457096 | SCV000542302 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-11-04 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg15108*) 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 variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 26084686, 30858397); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 404655). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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. |
| Blueprint Genetics | RCV000788734 | SCV000927955 | likely pathogenic | not provided | 2018-09-26 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004022552 | SCV005020864 | likely pathogenic | Cardiovascular phenotype | 2023-11-03 | criteria provided, single submitter | clinical testing | The p.R6043* variant (also known as c.18127C>T), located in coding exon 72 of the TTN gene, results from a C to T substitution at nucleotide position 18127. This changes the amino acid from an arginine to a stop codon within coding exon 72. This exon is located in the I-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_001267550:c.45322C>T, p.Arg15108*) has been detected in an individual from a dilated cardiomyopathy cohort (Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, |
RCV004764926 | SCV005375152 | likely pathogenic | Dilated cardiomyopathy 1G | 2024-01-06 | no assertion criteria provided | clinical testing |