ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.102523C>T (p.Arg34175Ter)

dbSNP: rs752697861
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000534053 SCV000639026 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg34175*) 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 (rs752697861, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy, congenital myopathy, and/or muscular dystrophy with scoliosis (PMID: 24105469, 25163546, 27868403, 28611029, 32998006, 36264615). This variant is also known as c.C75904T, p.R25302X. ClinVar contains an entry for this variant (Variation ID: 464497). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000624259 SCV000740491 likely pathogenic not provided 2017-07-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV003302825 SCV004005943 likely pathogenic Cardiovascular phenotype 2024-09-20 criteria provided, single submitter clinical testing The p.R25110* variant (also known as c.75328C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 75328. This changes the amino acid from an arginine to a stop codon within coding exon 185. This exon is located in the M-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 (also referred to as NM_001267550:c.102523C>T, p.R34175*) has been reported to co-occur with two other presumed truncating variants in TTN in individuals with childhood-onset skeletal myopathy with and without cardiomyopathy (Chauveau C et al. Hum Mol Genet, 2014 Feb;23:980-91; Park HJ et al. J Clin Neurol, 2017 Jan;13:116-118). This variant has also been detected in the presumed heterozygous state in an individual with dilated cardiomyopathy and in cohorts not selected for the presence of skeletal myopathy or cardiovascular disease; however, details were limited (Haggerty CM et al. Circulation. 2019 Jul;140(1):42-54; Haskell GT et al. Circ Cardiovasc Genet, 2017 Jun;10; Park J et al. Nat Med. 2021 Jan;27(1):66-72). 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though 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; 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 in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
PreventionGenetics, part of Exact Sciences RCV004735598 SCV005344192 pathogenic TTN-related disorder 2024-05-29 no assertion criteria provided clinical testing The TTN c.102523C>T variant is predicted to result in premature protein termination (p.Arg34175*). This variant occurs within the M-band region of the titin protein. RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). Truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer et al. 2017. PubMed ID: 27869827). ACMG recommends reporting TTN truncating variants in highly expressed exons due to the significant risk of cardiomyopathy (see ACMG statement in Miller et al. 2021. PubMed ID: 34012068). TTN truncating variants show incomplete and age-dependent penetrance in relation to autosomal dominant dilated cardiomyopathy. This variant has been reported in the heterozygous state in multiple unrelated individuals with dilated cardiomyopathy (Table S2, Haskell et al. 2017. PubMed ID: 28611029; Table 2, Anderson et al. 2020. PubMed ID: 32998006; Supplementary Table IV, Bourfiss et al. 2022. PubMed ID: 36264615). This variant has also been reported in the compound heterozygous state in an individual presenting with congenital core myopathy combined with primary heart disease and in two siblings with rigid spine syndrome and respiratory difficulty (Chauveau et al. 2014. PubMed ID: 24105469; Park et al. 2017. PubMed ID: 27868403). Many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy et al. 2013. PubMed ID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID: 27796757; Ge et al. 2019. PubMed ID: 31053406). Taken together, the c.102523C>T (p.Arg34175*) variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere RCV004764933 SCV005375100 likely pathogenic Dilated cardiomyopathy 1G 2024-01-06 no assertion criteria provided clinical testing

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