Submissions for variant NM_001267550.2(TTN):c.103758_103759del (p.Arg34586fs)

dbSNP: rs1689777278

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377688	SCV001575081	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg34586Serfs*32) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1031603). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). 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.
Ambry Genetics	RCV002395734	SCV002674161	likely pathogenic	Cardiovascular phenotype	2021-12-20	criteria provided, single submitter	clinical testing	The c.76563_76564delAG variant, located in coding exon 185 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 76563 to 76564, causing a translational frameshift with a predicted alternate stop codon (p.R25521Sfs*32). This exon is located in the M-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 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587127	SCV005076084	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-04-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.96054_96055delAG (p.Arg32018SerfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Nonsense, frameshift, and canonical splice-site variants in TTN are strongly associated with DCM when they affect exons encoding for the A-band region (PMIDs: 22335739, 24503780) and/or exons constitutively expressed (proportion spliced in [PSI]>0.9) in the primary cardiac isoforms (PMIDs: 25589632, 31216868, 32964742, 27869827), which is the case forthis variant (M band with a PSI score of 100%). The variant was absent in 248848 control chromosomes. To our knowledge, no occurrence of c.96054_96055delAG in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1031603). Based on the evidence outlined above, the variant was classified as likely pathogenic.