Submissions for variant NM_001267550.2(TTN):c.62217T>A (p.Tyr20739Ter)

dbSNP: rs727503586

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152265	SCV000201108	likely pathogenic	Primary dilated cardiomyopathy	2014-06-05	criteria provided, single submitter	clinical testing	The Tyr18171X variant in TTN has not been previously reported in individuals wit h cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 18171, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM and the majority occur in exons encoding for the A- band region of the protein (Herman 2012, Pugh 2014), where this variant is locat ed. In summary, although additional studies are required to fully establish its clinical significance, the Tyr18171X variant is likely pathogenic.
GeneDx	RCV000328776	SCV000330271	pathogenic	not provided	2024-06-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); This variant is associated with the following publications: (PMID: 25589632, 22335739)
Ambry Genetics	RCV000621593	SCV000736793	pathogenic	Cardiovascular phenotype	2023-05-30	criteria provided, single submitter	clinical testing	The p.Y11674* pathogenic mutation (also known as c.35022T>A), located in coding exon 131 of the TTN gene, results from a T to A substitution at nucleotide position 35022. This changes the amino acid from a tyrosine to a stop codon within coding exon 131. 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 alteration has been observed individuals with personal and/or family histories consistent with dilated cardiomyopathy (DCM) (Ambry internal data). 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 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 Jan;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642735	SCV000764422	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr20739*) 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: 165916). 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). 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.
Revvity Omics, Revvity	RCV000328776	SCV003812830	likely pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000328776	SCV000924995	likely pathogenic	not provided	2017-08-29	no assertion criteria provided	provider interpretation	Given that this is a truncating variant in the A-band of titin, and is 100% spliced in, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). To our knowledge, no literature has been published on this variant. 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: 179454235. LRG exon number is 305, N2BA transcript is 254. It is located in the A-band, 100% spliced in There is no variation at codon 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 88.2x in exomes and 36x in genomes.