Submissions for variant NM_001267550.2(TTN):c.53259del (p.Lys17753fs)

dbSNP: rs1389777522

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000532184	SCV000642437	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-22	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: 466636). This variant is also known as c.26640delA. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys17753Asnfs*7) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987598	SCV004803648	likely pathogenic	Primary familial dilated cardiomyopathy	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: TTN c.45555delA (p.Lys15185AsnfsX7) 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 (I band with a PSI score of 100%). The variant was absent in 248384 control chromosomes. c.45555delA has been reported in the literature in unspecified individuals affected with Dilated Cardiomyopathy (examples, Haas_2015, Jansweijer_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25163546, 27813223). ClinVar contains an entry for this variant (Variation ID: 466636). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786247	SCV000924992	likely pathogenic	not provided	2017-06-14	no assertion criteria provided	provider interpretation	Given that this is a truncating variant in the A-band, has been reported in another case with DCM and is absent from population databases, we consider this variant likely disease-causing, and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 1 unrelated case of DCM (not including this patient's family). There is weak case data: this variant is reported in 1 out of 639 northern European patients with DCM (Haas et al, 2015). It is known as c.26640delA or p.Lys8880fs in this paper. 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). 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. 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. They have a resource at cardiodb.org/titin that lists the relative inclusion of TTN exons in different isoforms and provides information to guide assessment of pathogenicity of specific truncation variants in the gene. Variants located in the A-band and present in cardiac isoforms of the protein were enriched in DCM patients versus controls. The genomic coordinates for this variant are chr2:179472156. LRG exon number is 278, N2BA transcript is 277. It is located in the A-band, 100% spliced in, in an IG-like domain. Another variant in the same exon has previously been reported in Herman et al 2012 in their DCM population. The lysine at codon 17753 is completely conserved across species, and neighboring amino acids are highly conserved as well. There is no variation at codon 17753 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 85x.