Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002650314 | SCV002976116 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-10-18 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg2021*) 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 clinical features of autosomal dominant dilated cardiomyopathy (PMID: 35572216); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 1940035). Studies have shown that this premature translational stop signal alters TTN gene expression (PMID: 35572216). This variant is located in the Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, 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, internal data). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004681520 | SCV005173482 | uncertain significance | Cardiovascular phenotype | 2024-04-15 | criteria provided, single submitter | clinical testing | The p.R1975* variant (also known as c.5923C>T), located in coding exon 26 of the TTN gene, results from a C to T substitution at nucleotide position 5923. This changes the amino acid from an arginine to a stop codon within coding exon 26. This exon is located in the near Z-disk region of the N2-B isoform of the titin protein and is not constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration has been reported in a family with left ventricular non-compaction (LVNC) (Dong XQ et al. J Geriatr Cardiol, 2022 Apr;19:301-314). 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). Based on the available evidence, the clinical significance of this variant remains unclear. |