2-178528273-C-T
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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.107377+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
TTN
NM_001267550.2 splice_donor
NM_001267550.2 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.65
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 2-178528273-C-T is Pathogenic according to our data. Variant chr2-178528273-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196723.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=9}. Variant chr2-178528273-C-T is described in Lovd as [Pathogenic]. Variant chr2-178528273-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.107377+1G>A | splice_donor_variant | ENST00000589042.5 | NP_001254479.2 | |||
| TTN-AS1 | NR_038272.1 | n.219+4637C>T | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.107377+1G>A | splice_donor_variant | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |||
| TTN-AS1 | ENST00000659121.1 | n.416+4637C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152170Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248508Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134800
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GnomAD4 exome AF: 0.0000370 AC: 54AN: 1461108Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 726780
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GnomAD4 genome 0.0000263 AC: 4AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:5Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 22, 2022 | PP1, PM3_strong, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2024 | Reported in the heterozygous state in a patient with dilated cardiomyopathy who did not harbor a second TTN variant (PMID: 25589632); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant for which RNA studies demonstrate alteration of normal gene transcription and expression (PMID: 28716623); Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (PMID: 17444505); This variant is associated with the following publications: (PMID: 32778822, 25214167, 32039858, 28716623, 29435569, 35081925, 35177841, 34135346, 36761691, 36264615, 25589632, 17444505) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 06, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 09, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 20, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Oct 05, 2021 | - - |
Neuromuscular disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2019 | The c.99673+1G>A variant in TTN, reported in the literature as c.107377+1G>A (NM_001267550.1), has been identified in the compound heterozygous state with truncating A-band variants in 3 individuals with limb girdle muscular dystrophy (LGMD) and 1 individual with mild progressive muscle weakness and dilated cardiomyopathy (DCM) and segregated with disease in 1 affected sibling. The heterozygous parents of these individuals were all reportedly unaffected (Harris 2017, Savarese 2018). It has been reported in the heterozygous state in 1 individual with DCM (Roberts 2015). It has also been identified in 3/248508 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 196723). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In addition, cDNA and Western blot analysis of patient cells demonstrated an impact to splicing (Harris 2017, Savarese 2018). Based on the available evidence, it is not clear if this variant is causative of autosomal dominant DCM, which is usually associated with truncating variants in the A-band. However, this variant meets criteria to be classified as pathogenic for autosomal recessive LGMD. ACMG/AMP criteria applied: PM3_Strong, PM2, PVS1_Moderate, PP1, PS3_Supporting. - |
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 14, 2024 | This sequence change affects a donor splice site in intron 361 of 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 (rs112188483, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 25214167, 25589632, 28716623, 36264615). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 196723). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 15, 2021 | - - |
Primary dilated cardiomyopathy Pathogenic:1
| 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. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2023 | The c.80182+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 188 of the TTN gene. Coding exon 188 is located in the M-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 nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant (also referred to as NM_001267550.1:c.107377+1G>A) has been reported to co-occur in trans and with phase unknown with other TTN truncating variants in unrelated and related individuals with skeletal myopathies with or without cardiac involvement and an individual from a dilated cardiomyopathy cohort (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Harris E et al. Neuromuscul Disord, 2017 Nov;27:1009-1017; Savarese M et al. JAMA Neurol, 2018 May;75:557-565; Savarese M et al. Genet Med, 2020 Dec;22:2029-2040). Functional studies have also indicated this variant to result in aberrant splicing (Harris E et al. Neuromuscul Disord, 2017 Nov;27:1009-1017). This alteration disrupts the canonical splice site and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site variants) in the M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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). Based on the majority of available evidence to date, this variant is pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
Splicing
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Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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