Submissions for variant NM_001267550.2(TTN):c.100127_100151dup (p.Ile33385fs)

dbSNP: rs1553503113

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599441	SCV000710753	likely pathogenic	not provided	2018-03-05	criteria provided, single submitter	clinical testing	The c.95204_95228dup25 likely 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 isoleucine 31744, changing it to a proline, and creating a premature stop codon at position 11 of the new reading frame, denoted p.Ile31744ProfsX11. 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, the c.95204_95228dup25 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). Moreover, this variant has not been observed in large population cohorts (Lek et al., 2016).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860231	SCV002314675	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-02-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile33385Profs*11) 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 504430). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017692	SCV004848590	likely pathogenic	Primary dilated cardiomyopathy	2021-11-01	criteria provided, single submitter	clinical testing	The p.Ile30817ProfsX11 variant in TTN has not been previously reported in individuals with cardiomyopathy but has been reported by other clinical laboratories in ClinVar (Variation ID: 504430). This variant is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 30817 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. TTN truncating variants encoded in constitutive exons (PSI >95%) have been found to be significantly associated with dilated cardiomyopathy (DCM) regardless of their position in titin (Roberts 2015 PMID:25589632, Schafer 2017 PMID:27869827). The p.Ile30817ProfsX11 variant is located in such a highly expressed exon in the A-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.