Submissions for variant NM_001267550.2(TTN):c.83515C>T (p.Arg27839Ter)

dbSNP: rs869312118

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000208903	SCV000189791	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469859	SCV000542819	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-03-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg27839*) 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: 25163546, 25589632; Invitae). This variant is also known as c.56896C>T p.R18966X. ClinVar contains an entry for this variant (Variation ID: 223386). 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.
CeGaT Center for Human Genetics Tuebingen	RCV002262799	SCV002544141	likely pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2, PS4:Moderate
Ambry Genetics	RCV004020570	SCV005020661	pathogenic	Cardiovascular phenotype	2023-12-29	criteria provided, single submitter	clinical testing	The p.R18774* pathogenic mutation (also known as c.56320C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 56320. This changes the amino acid from an arginine 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 (also referred to as NM_133437:c.56896C>T, p.R18966* and NM_001267550:c.83515C>T, p.Arg27839*) has been detected in individuals with dilated cardiomyopathy (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Haas J et al. Eur Heart J, 2015 May;36:1123-35a). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV002262799	SCV005325792	likely pathogenic	not provided	2024-03-11	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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34461741, 22335739, 25163546, 32160020, 32815318, 25589632)