Submissions for variant NM_001267550.2(TTN):c.3351dup (p.Ser1118fs)

dbSNP: rs2092847994

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001257237	SCV001433765	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1118Ilefs*21) 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 autosomal dominant dilated cardiomyopathy (PMID: 29093449, 32815318); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 978537). 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). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002224043	SCV002502812	likely pathogenic	not provided	2021-12-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004035373	SCV005020419	uncertain significance	Cardiovascular phenotype	2024-03-12	criteria provided, single submitter	clinical testing	The c.3213dupA variant, located in coding exon 18 of the TTN gene, results from a duplication of A at nucleotide position 3213, causing a translational frameshift with a predicted alternate stop codon (p.S1072Ifs*21). 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 variant (referred to as p1118I fs*21) was reported in an individual with features consistent with dilated cardiomyopathy (Marston S et al. PLoS One, 2015 Sep;10:e0138568). 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 alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004764961	SCV005400174	likely pathogenic	Dilated cardiomyopathy 1G	2024-09-22	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 near the Z-disk 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) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with cardiomyopathy (PMID: 29093449, Invitae person communication) and has been classified as both likely pathogenic and a VUS by clinical laboratories 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
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV004764961	SCV005375165	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing