2-178630240-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001267550.2(TTN):​c.44281+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,714 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: not found (cov: 33)
Exomes đť‘“: 0.0000034 ( 0 hom. )
Consequence
TTN
NM_001267550.2 splice_donor, intron
NM_001267550.2 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.86
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 Pathogenic. Variant got 11 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.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-178630240-C-T is Pathogenic according to our data. Variant chr2-178630240-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 223307.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1, Likely_pathogenic=5}. Variant chr2-178630240-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.44281+1G>A | splice_donor_variant, intron_variant | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.44281+1G>A | splice_donor_variant, intron_variant | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248288Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134662
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460714Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726616
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1G Pathogenic:2
| Likely pathogenic, no assertion criteria provided | clinical testing | Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere | Jan 06, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS4_Supporting+PVS1_Strong - |
Primary dilated cardiomyopathy Pathogenic:2
| 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2022 | The c.36577+1G>A variant in TTN has been reported in at least 3 individuals with dilated cardiomyopathy (DCM) and 1 individual with left ventricular systolic dysfunction (LVSD) (Roberts 2015 PMID: 25589632, Akhtar 2020 PMID: 32964742, Mazzarotto 2020 PMID: 31983221), and was absent in large population databases. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal dominant dilated cardiomyopathy. This variant meets criteria to be classified as likely pathogenic for autosomal dominant dilated cardiomyopathy. ACMG/AMP criteria applied: PVS1_Strong, PM2_Supporting, PS4_Supporting. - |
not provided Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2024 | Identified in patients with dilated cardiomyopathy referred for genetic testing at GeneDx and in the published literature (PMID: 25589632, 31983221, 32964742, 34315225, 33996946); Not observed at significant frequency in large population cohorts (gnomAD); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (PMID: 27625338, 27869827); This variant is associated with the following publications: (PMID: 31983221, 32964742, 34315225, 33996946, 27625338, 27869827, 25589632) - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 28, 2017 | c.44281+1G>A (splice donor) in the TTN gene (NM_001267550.2; chr2-179494967-C-T) - variant of uncertain significance Given that this variant is located in the I-band and there is no functional data to determine the impact of this splice variant, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The presence of truncating TTN variants in controls indicates that not all such variants can be presumed pathogenic. TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls (indicating that not all such variants are disease-causing). Therefore, truncating variants in the I-band of TTN are prevalent in the general population. In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families—pointing to the difficulty in determining variant pathogenicity for a specific truncating variant. Norton et al., identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. The variant has been seen in at least 1 unrelated cases of dilated cardiomyopathy (not including this patient's family). There is weak case data: This variant was submitted to ClinVar by the Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust - Endstage DCM. Roberts et al, 2015 performed cardiac phenotyping of 5267 affected and unaffected individuals as well as TTN DNA sequencing and RNA and protein analyses heart tissue. They have a resource at cardiodb.org/titin that lists the relative inclusion of TTN exons in different isoforms and provides information to guide assessment of pathogenicity of specific truncation variants in the gene. Variants located in the A-band and present in cardiac isoforms of the protein were enriched in DCM patients versus controls. This variant was reported in 1 patient in Roberts et al 2015 (CardioDB) and is classified as likely pathogenic. Phenotypic information on this individual is not available from the paper. Per Cardiodb, this is an essential splice site, is 98% spliced in, is present in the N2BA transcript and N2B transcript. However, this variant is located in the I-band of the titin protein. The genomic coordinates for this variant are chr179494967. LRG exon number is 240, N2BA transcript is 189. It is located in the I-band, 98% spliced in (100% spliced in in the LV tissue of 84 patients with DCM). Another variant in the same exon has previously been reported in the Robarts population: p.Pro14761Ser (c.44281C>T). The variant was reported online in 1 of 122,625 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 15,314 individuals of South Asian descent (MAF=0.003%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 23, 2023 | Variant summary: TTN c.36577+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. Nonsense, frameshift, and canonical splice-site variants in TTN are strongly associated with DCM when they affect exons encoding for the A-band region (PMIDs: 22335739, 24503780) and/or exons constitutively expressed (proportion spliced in [PSI]>0.9) in the primary cardiac isoforms (PMIDs: 25589632, 31216868, 32964742, 27869827), which is the case for this variant (located in the I-band with a PSI score of 100%). Several computational tools predict a significant impact on normal splicing: Four of four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248288 control chromosomes (gnomAD). c.36577+1G>A has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy (e.g. Roberts_2015, Akhtar_2020, Mazzarotto_2020, Enriquez_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32964742, 34315225, 31983221, 25589632). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifiying the variant as either likely pathogenic (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 17, 2021 | The c.17086+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 66 of the TTN gene. Exon 66 is located in the I-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 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 A-band are the most common cause of dilated cardiomyopathy (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). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). This variant has been reported (as NM_001267550.1: c.44281+1G>A) in a DCM cohort; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). As such, this alteration is classified as likely pathogenic. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 02, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 223307). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632, 31983221, 32964742, 34315225). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 239 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. - |
Primary dilated cardiomyopathy;C1837342:Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 09-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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_DL_spliceai
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