Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000534053 | SCV000639026 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg34175*) 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 present in population databases (rs752697861, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy, congenital myopathy, and/or muscular dystrophy with scoliosis (PMID: 24105469, 25163546, 27868403, 28611029, 32998006, 36264615). This variant is also known as c.C75904T, p.R25302X. ClinVar contains an entry for this variant (Variation ID: 464497). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). For these reasons, this variant has been classified as Pathogenic. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000624259 | SCV000740491 | likely pathogenic | not provided | 2017-07-25 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003302825 | SCV004005943 | likely pathogenic | Cardiovascular phenotype | 2023-05-18 | criteria provided, single submitter | clinical testing | The p.R25110* variant (also known as c.75328C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 75328. This changes the amino acid from an arginine to a stop codon within coding exon 185. This exon is located in the M-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 p.Arg34175*) has been reported to co-occur with two other presumed truncating variants in TTN in individuals with childhood-onset skeletal myopathy with and without cardiomyopathy (Chauveau C et al. Hum Mol Genet, 2014 Feb;23:980-91; Park HJ et al. J Clin Neurol, 2017 Jan;13:116-118). This variant has also been detected in the presumed heterozygous state in an individual with dilated cardiomyopathy and in cohorts not selected for the presence of skeletal myopathy or cardiovascular disease; however, details were limited (Haggerty CM et al. Circulation. 2019 Jul;140(1):42-54; Haskell GT et al. Circ Cardiovasc Genet, 2017 Jun;10; Park J et al. Nat Med. 2021 Jan;27(1):66-72). 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though 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; 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 in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. |