rs756433029
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001267550.2(TTN):c.4724_4728del(p.Met1575SerfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
TTN
NM_001267550.2 frameshift
NM_001267550.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.25
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-178777234-CTTTCA-C is Pathogenic according to our data. Variant chr2-178777234-CTTTCA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202501.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=13, Uncertain_significance=4, Pathogenic=1}. Variant chr2-178777234-CTTTCA-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.4724_4728del | p.Met1575SerfsTer6 | frameshift_variant | 27/363 | ENST00000589042.5 | NP_001254479.2 | |
TTN | NM_133379.5 | c.4724_4728del | p.Met1575SerfsTer6 | frameshift_variant | 27/46 | ENST00000360870.10 | NP_596870.2 | |
LOC101927055 | NR_120594.1 | n.315_319del | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000360870.10 | c.4724_4728del | p.Met1575SerfsTer6 | frameshift_variant | 27/46 | 5 | NM_133379.5 | ENSP00000354117 | ||
TTN | ENST00000589042.5 | c.4724_4728del | p.Met1575SerfsTer6 | frameshift_variant | 27/363 | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.4667_4671del | non_coding_transcript_exon_variant | 12/13 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251014Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135644
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461794Hom.: 0 AF XY: 0.0000261 AC XY: 19AN XY: 727204
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:15Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 30, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2024 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | TTN: PVS1:Strong, PM2, PS4:Moderate - |
Primary dilated cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2019 | 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. - |
Likely pathogenic, criteria provided, single submitter | research | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | Oct 08, 2014 | 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. - |
TTN-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 23, 2024 | 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. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 08, 2020 | - - |
Early-onset myopathy with fatal cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Hypertrophic cardiomyopathy 9 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | 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. - |
Dilated cardiomyopathy 1G Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Myopathy, myofibrillar, 9, with early respiratory failure Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Left ventricular noncompaction cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Klaassen Lab, Charite University Medicine Berlin | - | - - |
Tibial muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 23, 2016 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2023 | 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at