ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.62217T>A (p.Tyr20739Ter) (rs727503586)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2018-08-20 criteria provided, single submitter clinical testing The Y19098X variant in the TTN gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in one other individual referred for cardiac genetic testing at GeneDx. The Y19098X variant is not observed in large population cohorts (Lek et al., 2016). Y19098X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, Y19098X is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012).
Ambry Genetics RCV000621593 SCV000736793 likely pathogenic Cardiovascular phenotype 2020-09-16 criteria provided, single submitter clinical testing The p.Y11674* variant (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 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 Jan;49:46-53). As such, this alteration is classified as likely pathogenic.
Invitae RCV000642735 SCV000764422 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-09-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Tyr20739*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15253 amino acids of the 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: 165916). 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). ClinVar contains an entry for this variant (Variation ID: 165916). For these reasons, this variant has been classified as Likely Pathogenic.
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 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;, 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.

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