ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.86799_86802del (p.Glu28935_Gly28936insTer)

dbSNP: rs727504856
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156206 SCV000205922 likely pathogenic Primary dilated cardiomyopathy 2014-07-21 criteria provided, single submitter clinical testing The Gly26368X variant in TTN has been identified by our laboratory in 1 young ad ult with DCM. It was absent from large population studies. This variant is predi cted to cause a frameshift which leads to a premature termination codon at posit ion 26368. This alteration is then predicted to lead to a truncated or absent pr otein. Frameshift and other truncating variants in TTN are strongly associated w ith DCM and the majority occur in the A-band (Herman 2012, Pugh 2014), where thi s variant is located. In summary, although additional studies are required to fu lly establish its clinical significance, the Gly26368X variant is likely pathoge nic.
Genetic Services Laboratory, University of Chicago RCV000501735 SCV000597685 pathogenic not provided 2016-07-05 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000501735 SCV000704296 likely pathogenic not provided 2016-12-20 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000845492 SCV000987590 pathogenic Primary familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001204749 SCV001375969 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly28936*) 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 premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 31514951; Invitae). ClinVar contains an entry for this variant (Variation ID: 179417). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002354381 SCV002656486 likely pathogenic Cardiovascular phenotype 2024-08-22 criteria provided, single submitter clinical testing The c.59604_59607delAAAG variant, located in coding exon 153 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 59604 to 59607, causing a translational frameshift with a predicted alternate stop codon (p.G19871*). 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 variant (reported as c.86799_86802delAAAG, p.Thr28933fs2aaX) has been detected in a dilated cardiomyopathy (DCM) cohort (Gigli M et al. J. Am. Coll. Cardiol., 2019 09;74:1480-1490). 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 01;49:46-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000501735 SCV005198657 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004544450 SCV004794005 pathogenic TTN-related disorder 2023-11-14 no assertion criteria provided clinical testing The TTN c.86799_86802delAAAG variant is predicted to result in premature protein termination (p.Gly28936*). This variant was reported in a dilated cardiomyopathy cohort (online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the A-band region of the protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 95%-100%); however, this analysis in muscle tissue was not performed (Roberts et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Herman et al. 2012. PMID: 22335739; Roberts et al. 2015. PMID: 25589632). In summary, this variant is categorized as pathogenic for TTN-related disorders.

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