Submissions for variant NM_001267550.2(TTN):c.105190_105191del (p.Val35064fs)

dbSNP: rs770878165

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598788	SCV000710714	likely pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing	The c.100267_100268delGT 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 has not been observed in large population cohorts (Lek et al., 2016). The c.100267_100268delGT variant causes a shift in reading frame starting at codon valine 33423, changing it to a phenylalanine, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Val33423PhefsX4. 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. Other frameshift variants in the TTN gene have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014). However, c.100267_100268delGT is not 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). Other truncating variants in the M-band of titin, where this variant occurs, have been reported in association with an autosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents were reportedly healthy. Furthermore, other nonsense and frameshift TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012).
Ambry Genetics	RCV002413688	SCV002669070	likely pathogenic	Cardiovascular phenotype	2021-06-04	criteria provided, single submitter	clinical testing	The c.77995_77996delGT variant, located in coding exon 185 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 77995 to 77996, causing a translational frameshift with a predicted alternate stop codon (p.V25999Ffs*4). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Fulgent Genetics, Fulgent Genetics	RCV002491230	SCV002791153	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-11-22	criteria provided, single submitter	clinical testing
Invitae	RCV003767420	SCV004582063	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val35064Phefs*4) 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: 504393). 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, Invitae 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.