Submissions for variant NM_001267550.2(TTN):c.85090C>T (p.Arg28364Ter)

gnomAD frequency: 0.00001  dbSNP: rs770038577

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209383	SCV000189667	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.
Ambry Genetics	RCV000243897	SCV000320220	pathogenic	Cardiovascular phenotype	2021-12-07	criteria provided, single submitter	clinical testing	The p.R19299* pathogenic mutation (also known as c.57895C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 57895. 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 p.R28364* (c.85090C>T) and p.R26723* (c.80167C>T)) has been reported in dilated cardiomyopathy (DCM), left ventricular noncompaction, and early-onset atrial fibrillation cohorts (Roberts AM. Sci Transl Med 2015 Jan;7(270):270ra6; Choi SH et al. JAMA. 2018 12;320(22):2354-2364; Li S et al. J Am Heart Assoc, 2018 Oct;7:e009910; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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.
Invitae	RCV000476159	SCV000542814	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg28364*) 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 (no rsID available, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with atrial fibrillation and/or dilated cardiomyopathy (PMID: 25589632, 30535219; Invitae). ClinVar contains an entry for this variant (Variation ID: 223295). 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.
Blueprint Genetics	RCV000788393	SCV000927482	likely pathogenic	not provided	2017-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000788393	SCV001765215	pathogenic	not provided	2020-02-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic/likely pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID#223295; Landrum et al., 2016); 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 31983221, 25589632, 30535219)
Baylor Genetics	RCV003147409	SCV003835300	pathogenic	Tibial muscular dystrophy	2022-08-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147407	SCV003835303	pathogenic	Hypertrophic cardiomyopathy 9	2022-08-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147411	SCV003835394	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2022-08-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147412	SCV003835444	pathogenic	Early-onset myopathy with fatal cardiomyopathy	2022-08-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147408	SCV003836454	pathogenic	Dilated cardiomyopathy 1G	2022-08-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147410	SCV003836455	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-25	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000788393	SCV001978213	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000788393	SCV001979069	pathogenic	not provided		no assertion criteria provided	clinical testing