Submissions for variant NM_001267550.2(TTN):c.104092C>T (p.Arg34698Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504184

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177503	SCV000229379	likely pathogenic	not provided	2014-03-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000177503	SCV002021511	likely pathogenic	not provided	2019-10-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399536	SCV002673572	likely pathogenic	Cardiovascular phenotype	2024-01-10	criteria provided, single submitter	clinical testing	The p.R25633* variant (also known as c.76897C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 76897. 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 (referred to as p.R34698*, c.104092C>T) has been reported in the Jackson Heart Study cohort; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). This variant (referred to as p.R32130X, c.96388C>T) was also detected in compound heterozygosity with a TTN frameshift variant in a family with arthrogryposis multiplex congenita (Laquérriere A et al. Hum Mol Genet, 2014 May;23:2279-89). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764942	SCV004569696	likely 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.Arg34698*) 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 (rs727504184, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal recessive arthrogryposis multiplex congenita (PMID: 24319099, 33820833). This variant is also known as c.C96388T (p.R32130X). ClinVar contains an entry for this variant (Variation ID: 167754). 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). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209465	SCV004847624	likely pathogenic	Primary dilated cardiomyopathy	2019-01-25	criteria provided, single submitter	clinical testing	The p.Arg32130X variant in TTN has not been reported in individuals with TTN-associated diseases, such as dilated cardiomyopathy and neuromuscular conditions but has been identified in 1/15484 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has been reported in the compound heterozygous state with another loss-of-function variant in TTN in an individual with arthrogryposis multiplex congenita (AMC); however, the role of TTN variants in AMC is not well defined (Laquerriere 2014). It has been reported by clinical laboratories in ClinVar (variation ID #167754). This nonsense variant leads to a premature termination codon at position 32130, which is predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band (Herman 2012, Pugh 2014, Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Arg32130X variant is located in a highly expressed exon in the M-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2.
Fulgent Genetics, Fulgent Genetics	RCV005025234	SCV005655664	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	2024-03-11	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209465	SCV000189765	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	flagged submission	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.