Submissions for variant NM_001267550.2(TTN):c.47142_47143del (p.Cys15714_Glu15715delinsTer)

dbSNP: rs869312107

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204626	SCV001375839	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-09-13	criteria provided, single submitter	clinical testing	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. 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). This variant has not been reported in the literature in individuals with TTN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Cys15714*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789472	SCV005399667	likely pathogenic	Dilated cardiomyopathy 1G	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Likely pathogenic. Following criteria are met: 0102 - Loss of function is a 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 truncating 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 testing laboratory in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 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