Submissions for variant NM_001267550.2(TTN):c.27513del (p.Pro9172fs)

dbSNP: rs794729378

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184383	SCV000237008	uncertain significance	not provided	2014-05-20	criteria provided, single submitter	clinical testing	c.26562delT: p.Pro8855GlnfsX5 (P8855QfsX5) in exon 93 of the TTN gene (NM_001256850.1). The normal sequence with the base that is deleted in braces is: AAATT{T}CCAAG. The c.26562delT variant in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism to our knowledge. This variant causes a shift in reading frame starting at codon Proline 8855, changing it to a Glutamine, and creating a premature stop codon at position 5 of the new reading frame, denoted p.Pro8855GlnfsX5. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, c.26562delT is not 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). Other truncating variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s).
Eurofins Ntd Llc (ga)	RCV000184383	SCV000344385	uncertain significance	not provided	2018-01-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765156	SCV004587211	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro9172Glnfs*5) 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 premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive centronuclear myopathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 202514). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.