Submissions for variant NM_001267550.2(TTN):c.79145dup (p.Asn26382fs)

dbSNP: rs886041453

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000267089	SCV000330104	likely pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing	The c.74222dupA variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. c.74222dupA causes a shift in reading frame starting at codon Asparagine 24741, changing it to a Lysine, and creating a premature stop codon at position 31 of the new reading frame, denoted p.Asn24741LysfsX31. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.74222dupA is 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). Furthermore, this variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.74222dupA in the TTN gene is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005213246	SCV005853922	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-05-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn26382Lysfs*31) 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: 280205). 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.