Submissions for variant NM_001267550.2(TTN):c.48379_48382del (p.Phe16127fs)

dbSNP: rs1064796347

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486255	SCV000572966	pathogenic	not provided	2017-02-06	criteria provided, single submitter	clinical testing	The c.43456_43459delTTTA pathogenic variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. This variant causes a shift in reading frame starting at codon phenylalanine 14486, changing it to a lysine, and creating a premature stop codon at position 20 of the new reading frame, denoted p.Phe14486LysfsX20. This 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, the c.43456_43459delTTTA variant 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). Finally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766716	SCV004596829	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-05-17	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe16127Lysfs*20) 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 premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 33106378). 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). ClinVar contains an entry for this variant (Variation ID: 423289).
Lildballe Lab, Aarhus University Hospital	RCV004772934	SCV005200574	pathogenic	Primary dilated cardiomyopathy	2024-03-01	criteria provided, single submitter	research	PS4(m), PVS1(vs), PM2(sup)