Submissions for variant NM_001267550.2(TTN):c.59531_59570dup (p.Leu19857delinsPheSerTer)

dbSNP: rs1064792914

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473106	SCV000542413	likely pathogenic	Dilated cardiomyopathy 1G	2017-05-16	criteria provided, single submitter	clinical testing	This sequence change duplicates 40 nucleotides in exon 301 of the TTN mRNA (c.59531_59570dup), causing a frameshift at codon 19857. This creates a premature translational stop signal (p.Leu19857Phefs*3) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, 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). For these reasons, this variant has been classified as Likely Pathogenic.
Invitae	RCV001378780	SCV001576432	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-16	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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 404714). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu19857Phefs*3) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786256	SCV000925007	uncertain significance	not provided	2017-02-06	no assertion criteria provided	provider interpretation	Genetic testing for our patient was performed at Invitae. Given the lack of information on LVNC seen with this gene and variant type, what we know about TTN truncating variants in the general population, and lack of case data, we consider this variant a variant of uncertain significance - likely disease causing, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing") at this time. This is a novel variant and has not been reported in the literature. There are no ClinVar entry for this variant. Of note, there is limited literature associating the TTN gene with LVNC. 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 Chr2:179457162_179457201dup. LRG exon number is 300, N2BA transcript is 250. It is located in the A-band, 100% spliced in, in an Fibronectin type-III 31 domain. This variant is not present in the Genome Aggregation Data set (gnomAD; http://www.gnomad.broadinstitute.org), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. However, it should be noted that deletions and duplications of this size might not be well represented in the database due to technical sequencing limitations.