Submissions for variant NM_001267550.2(TTN):c.325C>T (p.Arg109Ter)

gnomAD frequency: 0.00001  dbSNP: rs150954246

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	RCV000209360	SCV000189797	uncertain significance	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.
GeneDx	RCV000578708	SCV000680822	uncertain significance	not provided	2018-08-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TTN gene. The R109X variant has not been published as pathogenic or been reported as benign to our knowledge. R109X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Additionally, other nonsense variants in the TTN gene have been reported in HGMD in association with dilated cardiomyopathy (Stenson et al., 2014). However, truncating TTN variants have been reported in approximately 3% of control alleles, and the R109X variant is not located in the A-band region of TTN, where the majority of truncating variants associated with DCM have been reported (Herman et al., 2010). Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Illumina Laboratory Services, Illumina	RCV000779292	SCV000915874	uncertain significance	TTN-Related Disorders	2018-12-05	criteria provided, single submitter	clinical testing	The TTN c.325C>T (p.Arg109Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg109Ter variant has been reported in one study in which it was noted to be present in a publicly available control population (Roberts et al. 2015). The variant has not been reported in association with disease. The p.Arg109Ter variant is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project though this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001221535	SCV001393587	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-06-13	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). ClinVar contains an entry for this variant (Variation ID: 223360). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is present in population databases (rs150954246, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg109*) 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	RCV002321826	SCV002606906	uncertain significance	Cardiovascular phenotype	2022-07-27	criteria provided, single submitter	clinical testing	The p.R109* variant (also known as c.325C>T), located in coding exon 3 of the TTN gene, results from a C to T substitution at nucleotide position 325. This changes the amino acid from an arginine to a stop codon within coding exon 3. This exon is located in the Z-disk 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 has been reported in a sudden unexplained death cohort (Giudicessi JR et al. Heart Rhythm O2, 2021 Oct;2:431-438). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with 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). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000578708	SCV003824879	uncertain significance	not provided	2019-04-18	criteria provided, single submitter	clinical testing