Submissions for variant NM_001267550.2(TTN):c.47692C>T (p.Arg15898Ter)

dbSNP: rs775186117

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209289	SCV000189775	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	RCV000813627	SCV000953994	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg15898*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632, 29961767). ClinVar contains an entry for this variant (Variation ID: 223371). 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). 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.
Revvity Omics, Revvity	RCV001781628	SCV002021471	likely pathogenic	not provided	2019-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004992085	SCV005525512	likely pathogenic	Cardiovascular phenotype	2024-11-22	criteria provided, single submitter	clinical testing	The p.R6833* variant (also known as c.20497C>T), located in coding exon 81 of the TTN gene, results from a C to T substitution at nucleotide position 20497. This changes the amino acid from an arginine to a stop codon within coding exon 81. 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_001267550.1:c.47692C>T, p.R15898*) was reported in an individual with features consistent with dilated cardiomyopathy (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Minoche AE et al. Genet Med, 2019 Mar;21:650-662). 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.
KTest Genetics, KTest	RCV001594386	SCV001499999	pathogenic	Dilated cardiomyopathy 1G		no assertion criteria provided	clinical testing
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	RCV001594386	SCV005375162	likely pathogenic	Dilated cardiomyopathy 1G	2024-01-06	no assertion criteria provided	clinical testing