ClinVar Miner

Submissions for variant NM_001256850.1(TTN):c.38621dupT (p.Phe12875Ilefs) (rs752856716)

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Total submissions: 2
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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,Partners HealthCare Personalized Medicine RCV000223318 SCV000271275 likely pathogenic Primary dilated cardiomyopathy 2015-06-26 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submitter clinical testing The p.Phe11948fs variant in TTN has been identified in 1 individual with DCM and VT (LMM unpublished data).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, which alters the protein’s amino acid sequence beginning at position 11948 and leads 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 truncating 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 in 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 Consortium (ExAC, http://exac.broadinstitute.org); however, for diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, although additional studies are required to fully establish its clinical significance, the p.Phe11948fs variant is likely pathogenic.

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