Submissions for variant NM_001267550.2(TTN):c.77933_77951del (p.Glu25978fs)

dbSNP: rs1553597801

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498951	SCV000590733	likely pathogenic	not provided	2017-06-27	criteria provided, single submitter	clinical testing	The c.73010_73028del19 likely pathogenic variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. This variant causes a shift in reading frame starting at codon glutamic acid 24337, changing it to a valine, and creating a premature stop codon at position 40 of the new reading frame, denoted p.Glu24337ValfsX40. This likely pathogenic variant 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 et al., 2012). However, c.73010_73028del19 is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Finally, the c.73010_73028del19 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379298	SCV001577073	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-20	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). ClinVar contains an entry for this variant (Variation ID: 432954). 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.Glu25978Valfs*40) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics	RCV002350112	SCV002645954	pathogenic	Cardiovascular phenotype	2024-08-26	criteria provided, single submitter	clinical testing	The c.50738_50756del19 pathogenic mutation, located in coding exon 153 of the TTN gene, results from a deletion of 19 nucleotides at nucleotide positions 50738 to 50756, causing a translational frameshift with a predicted alternate stop codon (p.E16913Vfs*40). 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 has been observed in at least one individual with a personal and/or family history that is consistent with dilated cardiomyopathy (Ambry internal data). 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). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.