Submissions for variant NM_001256850.1(TTN):c.38621dup (p.Phe12875fs)

gnomAD frequency: 0.00001  dbSNP: rs752856716

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184406	SCV000237031	uncertain significance	not provided	2014-10-10	criteria provided, single submitter	clinical testing	c.38621dupT: p.Phe12875IlefsX8 (F12875IfsX8) in exon 186 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are duplicated in braces is: GCTG{T}ATTT Although the c.38621dupT variant in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Phenylalanine 12875, changing it to an Isoleucine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Phe12875IlefsX8. 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. A c.38622dupA mutation (denoted c.38621_38622insA due to a difference in nomenclature), resulting in the same frameshift (denoted p.Ala12873fs), has been reported in a 30-year-old female with DCM and a history of ICD implantation (Herman et al., 2012). However, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). Furthermore, c.38621dupT 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). 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).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223318	SCV000271275	likely pathogenic	Primary dilated cardiomyopathy	2015-05-20	criteria provided, single submitter	clinical testing	The p.Phe11948fs variant in TTN has been identified in 1 individual with DCM and VT (LMM unpublished data). This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 11948 and lead s to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other tr uncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located i n an exon that is highly expressed in the heart (Roberts 2015). The p.Phe11948fs variant is located in I-band in the highly expressed exon 185. This variant has also been identified in 3/47886 European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org); however, for diseases with cli nical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, although additional studi es are required to fully establish its clinical significance, the p.Phe11948fs v ariant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519567	SCV003226768	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe14516Ilefs*8) 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 present in population databases (rs752856716, gnomAD 0.003%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 22335739); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 202536). 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, 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, internal data). 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.