ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.75663del (p.Lys25221fs) (rs1131691542)

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Total submissions: 3
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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 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-09-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Lys25221Asnfs*4). 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 429708). This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). 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.
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, 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 (, 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.

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