Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000185307 | SCV000238183 | uncertain significance | not specified | 2017-01-04 | criteria provided, single submitter | clinical testing | Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s). |
| ARUP Laboratories, |
RCV001812179 | SCV001473404 | uncertain significance | not provided | 2020-02-09 | criteria provided, single submitter | clinical testing | The TTN c.13205C>T; p.Ala4402Val variant (rs756976503; ClinVar Variation ID: 203228) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Ala4402Val variant cannot be determined with certainty. Pathogenic variants in the TTN gene are inherited both in an autosomal dominant and autosomal recessive manner and have been reported to cause a wide range of clinical phenotypes. TTN-associated conditions with cardiac manifestations include autosomal dominant dilated cardiomyopathy 1G (MIM: 604145), autosomal dominant familial hypertrophic cardiomyopathy 9 (MIM: 613765), and autosomal recessive Salih myopathy (MIM: 611705). Other genetic and/or environmental factors may influence the clinical phenotype. For recent information about properties and function of the titin protein see review authored by Linke and Hamdani (2014). References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. |
| Fulgent Genetics, |
RCV002485259 | SCV002787859 | uncertain significance | 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 | 2021-07-29 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV003335185 | SCV004046565 | uncertain significance | Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9 | 2023-03-08 | criteria provided, single submitter | clinical testing |