rs397517626
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001267550.2(TTN):c.56732dupA(p.Asp18911fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
TTN
NM_001267550.2 frameshift
NM_001267550.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.93
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-178598977-A-AT is Pathogenic according to our data. Variant chr2-178598977-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 47115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.56732dupA | p.Asp18911fs | frameshift_variant | 291/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.56732dupA | p.Asp18911fs | frameshift_variant | 291/363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
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GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460086Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4AN XY: 726244
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74256
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Asp18911Glufs*25) 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 (rs397517626, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with early-onset atrial fibrillation (PMID: 30535219). ClinVar contains an entry for this variant (Variation ID: 47115). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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. - |
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 28, 2022 | - - |
Dilated cardiomyopathy 1G Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 27, 2017 | This sequence change inserts 1 nucleotide in exon 291 of the TTN mRNA (c.56732dupA), causing a frameshift at codon 18911. This creates a premature translational stop signal (p.Asp18911Glufs*25) and is expected to result in a disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 31, 2016 | p.Asp16343Glufs (c.49028dupA) in the TTN gene (NM_133378.4) We've seen this variant in a family with familial DCM in our center, present in our affected patient and an affected second degree relative. Patient was tested at LMM so case data overlaps with LMM's. The variant was reported out as p.Asp16343fs (c.49028_49029insA) but per ClinVar (as of 2015) the current nomenclature would be as above. We re-reviewed the variant October 31st, 2016. I could find no new case data. The variant was novel at the time it was identified and still appears to be novel (as of October 2016). Per the LMM report, the variant would alter the reading frame and lead to introduction of a premature stop codon 25 amino acids downstream. The variant is in the A band. The variant is not listed in the ExAC, which currently includes variant calls on ~60,000 individuals (Oct 31 2016). Coverage at this site in ExAC is 42x. TTN is not yet available in gnomAD. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 11, 2013 | The Asp16343fs variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 16343 and lead to a pre mature termination codon 25 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM and the majority occur in the A -band (Herman 2012, LMM unpublished data), where this variant is located. In sum mary, this variant is likely to be pathogenic, though additional studies are req uired to fully establish its clinical significance. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at