Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825638 | SCV000967002 | likely pathogenic | Primary dilated cardiomyopathy | 2018-07-13 | criteria provided, single submitter | clinical testing | The p.Arg24941X variant in TTN has not been previously reported in individuals w ith DCM and was absent from large population studies. This variant has been repo rted in ClinVar (Variation ID 500011). This nonsense variant leads to a prematur e termination codon at position 24941, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly a ssociated with DCM if they impact 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). The p.Arg24941X variant is located in A-band in the highly expr essed exon 275. In summary, although additional studies are required to fully es tablish its clinical significance, the p.Arg24941X variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2. |
| Ambry Genetics | RCV002345917 | SCV002649387 | likely pathogenic | Cardiovascular phenotype | 2020-07-27 | criteria provided, single submitter | clinical testing | The p.R18444* variant (also known as c.55330C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 55330. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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. |
| Fulgent Genetics, |
RCV002495191 | SCV002803644 | likely pathogenic | 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 | 2021-10-09 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002538222 | SCV002958444 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-12-05 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg27509*) 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 left ventricular non-compaction, dilated cardiomyopathy (PMID: 33500567, 35629941, 36396199). This variant is also known as c.C55330T (p.R18444*). ClinVar contains an entry for this variant (Variation ID: 667023). 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). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005240626 | SCV003923279 | likely pathogenic | Primary familial dilated cardiomyopathy | 2025-02-10 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.74821C>T (p.Arg24941X), also reported as p.Arg18444X, results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.968 and a maximum cardiac muscle PSI of 1.000. The variant was absent in 248840 control chromosomes. c.74821C>T has been reported in the literature in individuals affected with clinical features of Dilated Cardiomyopathy and left ventricular non-compaction (example, Mazzarotoo_2021, Ravi_2022, Bourfiss_2022, Paldino_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33500567, 35629941, 36264615, 36396199). ClinVar contains an entry for this variant (Variation ID: 667023). Based on the evidence outline above, the variant has been classified as Likely Pathogenic for both autosomal dominant and autosomal recessive TTN-related conditions. |