Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000040169 | SCV000063860 | likely pathogenic | Primary dilated cardiomyopathy | 2015-05-07 | criteria provided, single submitter | clinical testing | The p.Arg1012X 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 1012, which is predicted to lead to a truncated or absent protein. Nonsense 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 expr essed in the heart (Roberts 2015). The p.Arg1012X variant is located in the high ly expressed exon 18 in the near Z-disk band. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg1012X variant is likely pathogenic. |
Neuro |
RCV000754723 | SCV000882610 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2J | 2018-10-08 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001314678 | SCV001505220 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-01-26 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 46899). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and left ventricular non-compaction (PMID: 24503780, 27532257, 29029073). This variant is present in population databases (rs397517547, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1012*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). |
Ambry Genetics | RCV002433512 | SCV002750860 | uncertain significance | Cardiovascular phenotype | 2023-01-09 | criteria provided, single submitter | clinical testing | The p.R966* variant (also known as c.2896C>T), located in coding exon 16 of the TTN gene, results from a C to T substitution at nucleotide position 2896. This changes the amino acid from an arginine to a stop codon within coding exon 16. This exon is located in the near Z-disk 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 (referred to as p.Arg1012X, c.3034C>T) was reported in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with 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). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |