Submissions for variant NM_001267550.2(TTN):c.64245G>A (p.Trp21415Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV003111528	SCV003762208	likely pathogenic	Dilated cardiomyopathy 1G	2023-02-03	criteria provided, single submitter	clinical testing	The c.64245G>A (p.Trp21415Ter) TTN variant has been reported in our laboratory in a 41-year-old male patient (diagnosis with 29 years) and his father (64 years, diagnosis with 60 years), both with a clinical diagnosis of Dilated CardioMyopathy. His 34-year-old brother, asymptomatic, did not have the variant. This variant has never been reported in TTN related-disorders. This variant was absent from large population studies (gnomAD no frequency). In summary, the available evidence for c.64245G>A (p.Trp21415Ter) TTN variant meets our criteria to be classified as Likely Pathogenic based upon its absence from controls and the clinical correlation in this patient´s phenotype
Labcorp Genetics (formerly Invitae), Labcorp	RCV003778676	SCV004609417	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp21415*) 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 reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 2429333). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003111528	SCV005398505	likely pathogenic	Dilated cardiomyopathy 1G	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature termination codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated A-band and the exon has a PSI score of 100% (PMID: 25589632). (I) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported as likely pathogenic by a clinical laboratory in an individual with DCM (ClinVar). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant segregated in two individuals with DCM and was absent in one unaffected individual (ClinVar, VCGS cohort). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign