ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.100587G>A (p.Trp33529Ter)

gnomAD frequency: 0.00001  dbSNP: rs1064793560
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482118 SCV000566444 pathogenic not provided 2023-11-07 criteria provided, single submitter clinical testing 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: 33226272, 22335739, 30535219, 34495297, 33906374, 29691892)
Invitae RCV000548615 SCV000642430 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-07-20 criteria provided, single submitter clinical testing This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 30535219, 33906374, 34495297; Invitae). 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). ClinVar contains an entry for this variant (Variation ID: 418978). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Trp33529*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics RCV002383911 SCV002674938 likely pathogenic Cardiovascular phenotype 2022-11-23 criteria provided, single submitter clinical testing The p.W24464* variant (also known as c.73392G>A), located in coding exon 184 of the TTN gene, results from a G to A substitution at nucleotide position 73392. This changes the amino acid from a tryptophan to a stop codon within coding exon 184. 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, also referred to as p.Trp33529* c.100587G>A , has been detected in an atrial fibrillation cohort and was reported to co-occur in trans with a TTN canonical I-band variant in a case with pediatric-onset cardiomyopathy from a cohort of patients with early onset hypotonia and/or congenital contractures (Choi SH et al. JAMA, 2018 12;320:2354-2364; Oates EC. Ann Neurol. 2018 Jun;83(6):1105-1124). 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 RCV002506161 SCV002798183 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 2022-02-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147474 SCV003835715 likely pathogenic Tibial muscular dystrophy 2022-11-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147472 SCV003835897 likely pathogenic Hypertrophic cardiomyopathy 9 2022-11-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147473 SCV003835898 likely pathogenic Dilated cardiomyopathy 1G 2022-11-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147476 SCV003835952 likely pathogenic Myopathy, myofibrillar, 9, with early respiratory failure 2022-11-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147477 SCV003836029 likely pathogenic Early-onset myopathy with fatal cardiomyopathy 2022-11-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147475 SCV003836083 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-11-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004535499 SCV004725778 pathogenic TTN-related disorder 2024-01-05 criteria provided, single submitter clinical testing The TTN c.100587G>A variant is predicted to result in premature protein termination (p.Trp33529*). This variant has been reported in patients with TTN-related conditions (Ware et al. 2021. PubMed ID: 33906374; Choi et al. 2018. PubMed ID: 30535219). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is located in the A-Band and RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts, demonstrating its clinical relevance (PSI of 100%, Roberts A.M. et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). Nonsense variants in this region of TTN are expected to be pathogenic. In the heterozygous state, early termination changes in the vicinity typically contribute to autosomal dominant cardiac-related phenotypes, whereas in combination with a second pathogenic variant in trans, they are associated with autosomal recessive muscular dystrophy phenotypes (Savarese et al. 2018. PubMed ID: 29435569). This variant is interpreted as pathogenic.

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