Submissions for variant NM_001267550.2(TTN):c.51833_51848del (p.Thr17278fs)

dbSNP: rs794729391

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184408	SCV000237033	pathogenic	not provided	2014-10-31	criteria provided, single submitter	clinical testing	c.46910_46925delCTATTACATGGATAAA: p.Thr15637ArgfsX36 (T15637RfsX36) in exon 223 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces is: CCAA{CTATTACATGGATAAA}GGAT. Although the c.46910_46925delCTATTACATGGATAAA mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Threonine 15637, changing it to an Arginine, and creating a premature stop codon at position 36 of the new reading frame, denoted p.Thr15637ArgfsX36. This mutation 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 D et al., 2012). However, c.46910_46925delCTATTACATGGATAAA is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.46910_46925delCTATTACATGGATAAA in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Mayo Clinic Laboratories, Mayo Clinic	RCV000184408	SCV002103200	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing	PM2, PS4_moderate, PVS1
Invitae	RCV002516950	SCV003350946	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-06-13	criteria provided, single submitter	clinical testing	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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 202538). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr17278Argfs*36) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.