Submissions for variant NM_001267550.2(TTN):c.5395dup (p.Ser1799fs)

dbSNP: rs1064796474

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521400	SCV000620156	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TTN gene. The c.5395dupA variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.5395dupA variant causes a shift in reading frame starting at codon serine 1799, changing it to a lysine, and creating a premature stop codon at position 10 of the new reading frame, denoted p.Ser1799LysfsX10. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, other truncating TTN variants have been reported in approximately 3% of control alleles and the c.5395dupA variant is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312475	SCV001502931	likely 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.Ser1799Lysfs*10) 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: 451454). 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.
Ambry Genetics	RCV002341227	SCV002642523	likely pathogenic	Cardiovascular phenotype	2025-03-04	criteria provided, single submitter	clinical testing	The c.5257dupA variant, located in coding exon 26 of the TTN gene, results from a duplication of A at nucleotide position 5257, causing a translational frameshift with a predicted alternate stop codon (p.S1753Kfs*10). This exon is located in the near Z-disk/I-band 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53; Akhtar MM et al. Circ Heart Fail, 2020 Oct;13:e006832; Massier M et al. Clin Genet, 2025 Jan). Based on the majority of available evidence to date, this variant is likely to be pathogenic.