ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.78178G>T (p.Glu26060Ter)

gnomAD frequency: 0.00001  dbSNP: rs794729289
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184265 SCV000236888 pathogenic not provided 2013-07-03 criteria provided, single submitter clinical testing The E24419X mutation in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. E24419X is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, E24419X is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, E24419X was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in DCM panel(s).
Eurofins Ntd Llc (ga) RCV000184265 SCV000344817 likely pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
Invitae RCV000703198 SCV000832086 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu26060*) 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 present in population databases (rs794729289, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or early-onset atrial fibrillation (PMID: 30535219, 34495297; Invitae). ClinVar contains an entry for this variant (Variation ID: 202409). 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.
AiLife Diagnostics, AiLife Diagnostics RCV000184265 SCV002501934 pathogenic not provided 2022-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV002336475 SCV002642449 likely pathogenic Cardiovascular phenotype 2022-11-17 criteria provided, single submitter clinical testing The p.E16995* variant (also known as c.50983G>T), located in coding exon 153 of the TTN gene, results from a G to T substitution at nucleotide position 50983. This changes the amino acid from a glutamic acid to a stop codon within coding exon 153. 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 has been detected in an early onset atrial fibrillation cohort (Choi SH et al. JAMA, 2018 12;320:2354-2364). 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 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 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002503725 SCV002814437 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-08-30 criteria provided, single submitter clinical testing

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