Submissions for variant NM_001267550.2(TTN):c.75663del (p.Lys25221fs)

dbSNP: rs1131691542

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493831	SCV000582341	pathogenic	not provided	2015-08-24	criteria provided, single submitter	clinical testing	Although the c.70740delA deletion in the TTN gene has not been reported to our knowledge, this variantcauses a shift in reading frame starting at codon Lysine 23580, changing it to an Asparagine, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Lys23580AsnfsX4. This deletion is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, the c.70740delA variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other frameshift variants in the TTN gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Although truncating TTN variants have been observed in approximately 3% of control alleles (Herman et al., 2012), the c.70740delA deletion is located in the A-band of titin, where the majority of truncating variants associated with DCM have been reported (Herman et al., 2012). In summary, c.70740delA in the TTN gene is interpreted as a pathogenic variant.
Invitae	RCV000702013	SCV000830840	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys25221Asnfs*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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of TTN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 429708). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002341167	SCV002638078	likely pathogenic	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The c.48468delA variant, located in coding exon 153 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 48468, causing a translational frameshift with a predicted alternate stop codon (p.K16156Nfs*4). 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 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 majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496896	SCV002809886	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	2021-11-23	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000493831	SCV000924993	likely pathogenic	not provided	2016-09-22	no assertion criteria provided	provider interpretation	-p.Lys23580AsnfsX4 (c.70740delA) in exon 276 of the TTN gene (NM_001256850.1 - N2BA principle cardiac long isoform) We have seen this variant in a person with DCM. This variant is of a type that has associated with disease in this gene. We consider this variant likely pathogenic with the caveat that there may be other factors that influence penetrance of the variant, including other possible genetic causes in the family. Therefore, we will offer predictive testing for this variant with careful counseling that presence of the variant will likely increase risk for DCM, but absence of the variant doesn't necessarily rule out the familial risk. The variant has not been published. It is not present in ClinVar. Based on the data reviewed below, we consider this variant to be a likely contributor to the DCM in this family. The presence of truncating TTN variants in controls indicates that not all such variants can be presumed pathogenic. TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls (indicating that not all such variants are disease-causing). While truncating variants in TTN have been associated with disease, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al. 2012). In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families—pointing to the difficulty in determining variant pathogenicity for a specific truncating variant. Norton et al., identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. One of these variants was in exon 276 of N2BA (A-band, 100% spliced in, but also had a 2nd published variant with functional data; the other was in exon 46 of N2BA (I-band, 100% spliced in). Roberts et al, 2015 performed cardiac phenotyping of 5267 affected and unaffected individuals as well as TTN DNA sequencing and RNA and protein analyses heart tissue. Variants located in the A-band and present in cardiac isoforms of the protein were enriched in DCM patients versus controls. Per the Titin Variants in DCM site on cardiodb.org, Lys23580AsnfsX4 (chr2:179435196) is located in the A band and exon 276 of the N2BA transcript is 100% spliced-in. There is no variation at position chr2:179435196 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 9/23/16). The average coverage at that site in ExAC is mean ~40x and median ~35x.