Submissions for variant NM_001267550.2(TTN):c.94180delinsTCTAGCAG (p.Pro31394fs)

dbSNP: rs727503547

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152184	SCV000200921	likely pathogenic	Primary dilated cardiomyopathy	2014-07-09	criteria provided, single submitter	clinical testing	The Pro28826fs variant in TTN has not been reported in individuals with cardiomy opathy or in large population studies. This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 288 26 and lead to a premature termination codon 12 amino acids downstream. This alt eration is then predicted to lead to a truncated or absent protein. Frameshift a nd other truncating variants in TTN are strongly associated with DCM, particular ly if they are located in the exons encoding for the A-band region of the protei n (Herman 2012, Pugh 2014), where this variant is located. In summary, although additional studies are required to fully establish its clinical significance, th e Pro28826fs variant is likely pathogenic.
GeneDx	RCV000184361	SCV000236986	pathogenic	not provided	2023-08-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012)
AiLife Diagnostics, AiLife Diagnostics	RCV000184361	SCV002502878	likely pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362796	SCV002665370	likely pathogenic	Cardiovascular phenotype	2021-11-30	criteria provided, single submitter	clinical testing	The c.66985delCinsTCTAGCAG variant, located in coding exon 166 of the TTN gene, results from the deletion of one nucleotide and insertion of 8 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.P22329Sfs*12). This exon is located in the A-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 alteration 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 (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). 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). As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002492565	SCV002780192	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-08-19	criteria provided, single submitter	clinical testing
Invitae	RCV003764931	SCV004581498	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-07-06	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 466668). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This sequence change creates a premature translational stop signal (p.Pro31394Serfs*12) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.