ClinVar Miner

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

dbSNP: rs756433029
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Total submissions: 17
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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 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.

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