2-178642236-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_ModeratePP5
The NM_001267550.2(TTN):c.40558+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000943 in 1,579,460 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
Consequence
NM_001267550.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.40558+1G>A | splice_donor_variant, intron_variant | Intron 219 of 362 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.40558+1G>A | splice_donor_variant, intron_variant | Intron 219 of 362 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.0000395 AC: 6AN: 151792Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000442 AC: 9AN: 203664Hom.: 0 AF XY: 0.0000366 AC XY: 4AN XY: 109208
GnomAD4 exome AF: 0.000100 AC: 143AN: 1427668Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 76AN XY: 706942
GnomAD4 genome 0.0000395 AC: 6AN: 151792Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74114
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Canonical splice site variant with an unclear effect on protein function; 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); Identified in an individual with sudden death and history of DCM and atrial fibrillation who also harbored a pathogenic variant in the LMNA gene (PMID: 28333919); This variant is associated with the following publications: (PMID: 26701604, 23975875, 25589632, 31691645, 34461741, 35177841, 33226272, 34135346, 37652022, 30535219, 22335739, 24503780, 27625338, 27869827, 28333919) -
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Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
This sequence change affects a donor splice site in intron 219 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs368219776, gnomAD 0.01%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 22335739, 28333919, 30535219; internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 223256). 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 I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, 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, internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Primary familial dilated cardiomyopathy Pathogenic:1
Variant summary: TTN c.32854+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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TTN function. One computational tool predicts the variant abolishes the 5' donor site. However, these predictions have yet to be confirmed by functional studies. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.875 and a maximum cardiac muscle PSI of 1.000. The variant allele was found at a frequency of 4.4e-05 in 203664 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. c.32854+1G>A has been reported in the literature in the heterozygous state in several individuals affected with Dilated Cardiomyopathy (e.g. Herman_2012, Bagnall_2017), however in one of these cases other potentially causal co-occurring variants were also present. In addition, the variant was also reported in 3 / 13,131 asymptomatic individuals aged 70 years and older without a history of atherothrombotic cardiovascular disease events in the ASPREE study (Lacaze_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25589632, 30535219, 35177841, 28333919, 33226272, 22335739, 34135346, 37652022). ClinVar contains an entry for this variant (Variation ID: 223256). Based on the evidence outlined above, the variant was classified as Likely Pathogenic for both autosomal dominant and autosomal recessive TTN-related conditions. -
not specified Uncertain:1
The c.32854+1G>A variant in TTN has been reported in 1 individual with DCM, and segregated with disease in 1 affected relative (Herman 2012). This variant has also been identified in 4/15632 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368219776). The c.32854+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice and other truncating variants in TTN are strongly associated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014). Variants in the I-band, where the c.32854+1G>A variant is located, occur at a greater frequency in controls than in individuals with DCM (Pugh 2014). This decreases the likelihood, but does not rule out that this variant has a role in disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.32854+1G>A variant is uncertain. -
Dilated cardiomyopathy 1G Uncertain:1
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Cardiomyopathy Uncertain:1
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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 Uncertain:1
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Primary dilated cardiomyopathy Uncertain:1
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 Uncertain:1
The c.13363+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 46 of the TTN gene. Coding exon 46 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 variant (also referred to as c.35635+1G>A and c.40558+1G>A) has been reported in dilated cardiomyopathy cohorts, but also in population-based cohorts and cohorts not selected for the presence of cardiomyopathy (Herman DS et al. N Engl J Med. 2012 Feb;366(7):619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7(270):270ra6; Connell PS et al. Circ Genom Precis Med. 2021 Feb;14(1):e003131; Lacaze P et al. NPJ Genom Med. 2021 Jun;6(1):51). This variant was detected in a sudden death victim reported to have dilated cardiomyopathy who also had variants in other cardiac-related genes, and this alteration did not segregate with disease in the family (Bagnall RD et al. Genet Med. 2017 Oct;19(10):1127-1133). This variant has also been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA. 2018 12;320(22):2354-2364). 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing and often result in a transcript encoding a truncated protein. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (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;366:619-28; Roberts AM et al. Sci Transl Med. 2015;7:270ra6; Schafer S et al. Nat. Genet. 2017;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). Since the exact splicing impact of this alteration is unknown and supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at