Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000214051 | SCV000271289 | likely pathogenic | Primary dilated cardiomyopathy | 2015-04-18 | criteria provided, single submitter | clinical testing | The p.Asn4301X variant in TTN has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 4301 (located in the I-band), which i s predicted to lead to a truncated or absent protein. Nonsense and other truncat ing variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). This variant is locat ed in such a highly expressed exon in the I-band. In summary, although additiona l studies are required to fully establish its clinical significance, the Asn4301 X variant is likely pathogenic. |
| Labcorp Genetics |
RCV001220812 | SCV001392824 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-07-11 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asn4539*) 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 autosomal dominant dilated cardiomyopathy (PMID: 25163546, 32371228, 37652022; Invitae); however, the role of the variant in this condition is currently unclear. This variant is also known as c.13102_13103insT (p.N4368_V4369delinsX) and p.Asn4176*. ClinVar contains an entry for this variant (Variation ID: 228310). 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, Invitae 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, Invitae 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. |
| Ambry Genetics | RCV003165535 | SCV003856860 | likely pathogenic | Cardiovascular phenotype | 2024-11-11 | criteria provided, single submitter | clinical testing | The c.12525dupT variant, located in coding exon 44 of the TTN gene, results from a duplication of T at nucleotide position 12525, causing a translational frameshift with a predicted alternate stop codon (p.N4176*). 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 (referred to as c.13102_13103insT, p.N4368_V4369delinsX) has been detected in a dilated cardiomyopathy (DCM) cohort (Haas J et al. Eur Heart J, 2015 May;36:1123-35a). 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 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. |
| Fulgent Genetics, |
RCV005025349 | SCV005655305 | uncertain significance | 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 | 2024-03-04 | criteria provided, single submitter | clinical testing |