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

dbSNP: rs756433029

Total submissions: 18

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	2024-04-22	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 (PMID: 25589632, 30535219, 31112426, 31983221, 34540771, 36264615); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 30535219, 31983221, 34540771, 31112426, 36264615, 35177841, 33449170, 25589632)
Labcorp Genetics (formerly Invitae), Labcorp	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	2023-10-19	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 (also referred to as NM_001267550:c.4724_4728delTGAAA, p.Met1575Serfs*6) has been detected in individuals from dilated cardiomyopathy (DCM), left ventricular noncompaction, and early onset atrial fibrillation cohorts, as well as in individuals not known to have cardiovascular disease; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Choi SH et al. JAMA, 2018 12;320:2354-2364; Jansen M et al. Circ Genom Precis Med. 2019 May;12(5):e002436; Schultze-Berndt A et al. Front Pediatr. 2021 Sep;9:722926; Bourfiss M et al. Circ Genom Precis Med. 2022 Dec;15(6):e003704). This variant has also been detected in a proband with centronuclear myopathy (Rees M et al. Acta Neuropathol. 2021 Mar;141(3):431-453).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 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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209800	SCV004847617	likely pathogenic	Primary dilated cardiomyopathy	2019-02-22	criteria provided, single submitter	clinical testing	The p.Met1575SerfsX6 variant in TTN has been reported in 1 individual with DCM (Roberts 2015) and has been identified in 3/128802 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID #202501). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1575 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Met1575SerfsX6 variant is located in a highly expressed exon in the near Z-disk region. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2.
PreventionGenetics, part of Exact Sciences	RCV004734812	SCV005360208	likely pathogenic	TTN-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The TTN c.4724_4728del5 variant is predicted to result in a frameshift and premature protein termination (p.Met1575Serfs*6). This variant has been reported in a cohort study of individuals with dilated cardiomyopathy (Table S1, Roberts et al. 2015. PubMed ID: 25589632), as well as in one individual with early onset atrial fibrillation (eTable 5, Choi et al. 2018. PubMed ID: 30535219). This variant is located near the Z-disk and I-band junction. Other nearby loss-of-function variants have been reported in cases of autosomal recessive TTN-related myopathies (c.3880_3884delGATTC in Yu et al. 2019. PubMed ID: 31353864; c.4579delG in Töpf et al. 2020. PubMed ID: 32528171; c.4819G>T at PreventionGenetics). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals but occur more frequently in exons with low PSI values (Roberts et al. 2015. PubMed ID: 25589632; Herman et al. 2012. PubMed ID: 22335739). However, many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy et al. 2013. PMID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, the c.4724_4728del variant is likely pathogenic for both autosomal recessive and dominant TTN-related disorders.