Submissions for variant NM_001267550.2(TTN):c.4724_4728del (p.Met1575fs)

dbSNP: rs756433029

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209800	SCV000189630	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.
GeneDx	RCV000184370	SCV000236995	likely pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Reported in association with DCM, LVNC and early-onset atrial fibrillation in patients tested at GeneDx and in published literature (Roberts et al., 2015; Choi et al., 2018; Jansen et al., 2019; Mazzarotto et al., 2020; Schultze-Berndt et al., 2021; Bourfiss et al., 2022); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30535219, 31983221, 34540771, 31112426, 36264615, 35177841, 33449170, 25589632)
Invitae	RCV000226275	SCV000286681	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met1575Serfs*6) 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 (rs756433029, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or TTN-related conditions (PMID: 25589632, 30535219, 31112426, 31983221, 33449170; Invitae). ClinVar contains an entry for this variant (Variation ID: 202501). This variant is located in the Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, Invitae internal data). 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506593	SCV000605482	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000184370	SCV000861809	uncertain significance	not provided	2018-06-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798647	SCV002042530	likely pathogenic	Cardiomyopathy	2020-05-08	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV002056967	SCV002495736	likely pathogenic	Left ventricular noncompaction cardiomyopathy		criteria provided, single submitter	research
AiLife Diagnostics, AiLife Diagnostics	RCV000184370	SCV002502831	likely pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336478	SCV002638587	uncertain significance	Cardiovascular phenotype	2021-04-23	criteria provided, single submitter	clinical testing	The c.4586_4590delTGAAA variant, located in coding exon 25 of the TTN gene, results from a deletion of 5 nucleotides at nucleotide positions 4586 to 4590, causing a translational frameshift with a predicted alternate stop codon (p.M1529Sfs*6). This exon is located in the near 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 variant has been detected in individuals from dilated cardiomyopathy and early onset atrial fibrillation cohorts; however, details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Choi SH et al. JAMA, 2018 12;320:2354-2364). 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). Based on available evidence to date, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003333042	SCV004041252	likely pathogenic	Hypertrophic cardiomyopathy 9	2023-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333045	SCV004041394	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333044	SCV004041493	likely pathogenic	Tibial muscular dystrophy	2023-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333046	SCV004041494	likely pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2023-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333043	SCV004041528	likely pathogenic	Dilated cardiomyopathy 1G	2023-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333047	SCV004041559	likely pathogenic	Early-onset myopathy with fatal cardiomyopathy	2023-05-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000184370	SCV004704047	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2, PS4:Moderate