rs202234172
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePP3_Strong
The NM_001267550.2(TTN):c.31763-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 1,612,568 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 0 hom. )
Consequence
TTN
NM_001267550.2 splice_acceptor
NM_001267550.2 splice_acceptor
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.57
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 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 7.686893E-4 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of 6, new splice context is: tcaaaaactttaaatcccAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.31763-1G>A | splice_acceptor_variant | ENST00000589042.5 | |||
| LOC124907912 | XR_007087321.1 | n.1760C>T | non_coding_transcript_exon_variant | 1/2 | |||
| LOC124906100 | XR_007087318.1 | n.2186-23857C>T | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.31763-1G>A | splice_acceptor_variant | 5 | NM_001267550.2 | P1 | |||
| TTN-AS1 | ENST00000659121.1 | n.503-44607C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes 0.000447 AC: 68AN: 152092Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000338 AC: 84AN: 248510Hom.: 0 AF XY: 0.000252 AC XY: 34AN XY: 134780
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GnomAD4 exome AF: 0.000531 AC: 776AN: 1460476Hom.: 0 Cov.: 31 AF XY: 0.000497 AC XY: 361AN XY: 726510
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GnomAD4 genome 0.000447 AC: 68AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28AN XY: 74314
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 01, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2024 | Reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and peripartum cardiomyopathy (PMID: 26735901, 23396983, 25589632, 29961767, 33874732, 32815318); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Also known as c.28031-1 G>A, c.31763-1G>A, and g.179554624 C>T due to the use of alternate transcripts and/or nomenclature; This variant is associated with the following publications: (PMID: 23396983, 25589632, 26777568, 24980681, 29961767, 30724488, 33874732, 27625338, 27869827, 33106378, 35177841, 31691645, 30535219, 29988065, 27813223, 26735901, 32815318, 33226272) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2017 | - - |
not specified Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2018 | Variant classified as Uncertain Significance - Favor Benign. The c.28031-1G>A va riant in TTN has been reported in at least 1 individual with peripartum cardiomy opathy, 2 individuals with DCM, and 1 individual with interventricular conductio n delay (Ware 2016, Roberts 2015, Akinrinade 2016, LMM data). This variant has a lso been identified in 0.07% (83/126420) of European chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202234172 ), which reduces the likelihood that the variant causes disease. This variant oc curs in the invariant region (+/- 1,2) of the splice consensus sequence and is p redicted to cause altered splicing leading to an abnormal or absent protein. Tru ncating variants in TTN are strongly associated with DCM, if they impact the exo ns encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exo n that is highly expressed in the heart (Roberts 2015). Variants in the I-band, where the c.28031-1G>A variant is located, are less likely to be disease causing (Pugh 2014, Roberts 2015). In summary, while the clinical significance of the c .28031-1G>A variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS4_Supporting; BS1. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 06, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2023 | Variant summary: TTN c.28031-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. One computational tool predicts the variant abolishes a 3 acceptor site and two predict the variant creates a cryptic exonic one. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 248510 control chromosomes, predominantly at a frequency of 0.00068 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.28031-1G>A has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, peripartum cardiomyopathy, atrial fibrillation, ventricular arrhythmia, heart failure, mitral valve disease, and supraventricular tachycardia (Lopes_2013, Roberts_2015, Ware_2016, Jansweijer_2017, Choi_2018, Verhagen_2018, Minoche_2019, Choi_2020, Goli_2021, Vissing_2021, Jurgens_2022), but it was also detected in multiple controls (Choi_2018, Choi_2020, Jurgens_2022). In at least one of the studies the variant was found to incompletely segregate with disease in affected members of one family (Minoche_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance, two ClinVar submitters (evaluation after 2014) cite it as likely benign, and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. The variant is located within the I-band region of titin, adjacent to a symmetrical exon that is not constitutively expressed. Heterozygous mutations that truncate full-length titin (TTNtv, titin truncating variants) are the most common genetic cause for severe and familial dilated cardiomyopathy (DCM). Nevertheless, TTNtv also occur in approximately 2% of individuals without overt cardiomyopathy. Importantly, TTNtv associated with DCM are predominantly located in the A-band region (PMID 22335739, 25589632). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Primary dilated cardiomyopathy Pathogenic:1Uncertain:1
| Uncertain significance, 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 with intermediate levels of cardiac expression. 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. - |
| 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 with intermediate levels of cardiac expression. 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. - |
Tip-toe gait Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Nov 24, 2021 | Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. - |
Dilated cardiomyopathy 1G Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | - - |
Cardiomyopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 06, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
Splicing
Name
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_AG_spliceai
Position offset: -7
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at