Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Cardiovascular Biomedical Research Unit, |
RCV000209178 | SCV000189631 | likely pathogenic | Primary dilated cardiomyopathy | 2014-10-08 | criteria provided, single submitter | research | This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. |
| Laboratory for Molecular Medicine, |
RCV000209178 | SCV000271285 | likely pathogenic | Primary dilated cardiomyopathy | 2018-10-10 | criteria provided, single submitter | clinical testing | The p.Ala2770fs variant in TTN has been reported in 1 individual with DCM (Rober ts 2015) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2770 and leads to a premature termination codon 4 amino acids downs tream. This alteration is then predicted to lead to a truncated or absent protei n. Frameshift and other truncating 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 (Rober ts 2015). The p.Ala2770fs variant is located in the I-band in the highly express ed exon 35. In summary, although additional studies are required to fully establ ish its clinical significance, the p.Ala2770fs variant is likely pathogenic. ACM G/AMP Criteria applied: PVS1, PM2. |
| Invitae | RCV001853332 | SCV002159489 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ala2770Hisfs*4) 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 individual(s) with clinical features of dilated or noncompaction cardiomyopathy (PMID: 25589632, 30847666, 31983221, 36264615). ClinVar contains an entry for this variant (Variation ID: 223266). 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 | RCV003165514 | SCV003856822 | likely pathogenic | Cardiovascular phenotype | 2022-12-20 | criteria provided, single submitter | clinical testing | The c.8169_8170delTG variant, located in coding exon 33 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 8169 to 8170, causing a translational frameshift with a predicted alternate stop codon (p.A2724Hfs*4). 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 c.8307_8308delTG, p.A2770Hfs*4) has been detected in an individual from a dilated cardiomyopathy (DCM) cohort, a DCM genetic testing diagnostic referral cohort, and in an individual indicated to have noncompaction cardiomyopathy (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). 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. |