rs587780494
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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.6555_6556insTGTAAGGAAACAGACA(p.Lys2186fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
TTN
NM_001267550.2 frameshift
NM_001267550.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.95
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 2-178775155-T-TTGTCTGTTTCCTTACA is Pathogenic according to our data. Variant chr2-178775155-T-TTGTCTGTTTCCTTACA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130679.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=3, Likely_pathogenic=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
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TTN | NM_001267550.2 | c.6555_6556insTGTAAGGAAACAGACA | p.Lys2186fs | frameshift_variant | 29/363 | ENST00000589042.5 | NP_001254479.2 | |
TTN | NM_133379.5 | c.6555_6556insTGTAAGGAAACAGACA | p.Lys2186fs | frameshift_variant | 29/46 | ENST00000360870.10 | NP_596870.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.6555_6556insTGTAAGGAAACAGACA | p.Lys2186fs | frameshift_variant | 29/363 | 5 | NM_001267550.2 | ENSP00000467141.1 | ||
TTN | ENST00000360870.10 | c.6555_6556insTGTAAGGAAACAGACA | p.Lys2186fs | frameshift_variant | 29/46 | 5 | NM_133379.5 | ENSP00000354117.4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250662Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135452
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461698Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727156
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74350
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 10, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2021 | Reported in association with early-onset atrial fibrillation in a whole-genome sequencing cohort (Choi et al., 2018); Reported in ClinVar (ClinVar Variant ID# 130679; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30535219) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Oct 06, 2021 | - - |
Dilated cardiomyopathy 1G Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 11, 2023 | The TTN c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186CysfsTer15) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is located in exon 29 of the meta transcript of titin within the I-band, which is highly expressed in cardiac tissue (PMID: 25589632). In a meta-analysis of TTN truncating variants in DCM patients and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio = 19.0) (PMID: 27869827). This variant is reported in the Genome Aggregation Database in seven alleles at a frequency of 0.000054 in the European (non-Finnish) population (version 2.1.1). Based on the available evidence, the c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186CysfsTer15) variant is classified as likely pathogenic for dilated cardiomyopathy. - |
Tibial muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 30, 2013 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2023 | The c.6417_6418ins16 variant, located in coding exon 27 of the TTN gene, results from an insertion of 16 nucleotides (TGTAAGGAAACAGACA) at position 6417, causing a translational frameshift with a predicted alternate stop codon (p.K2140Cfs*15). This exon 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 (referred to as p.Lys2186fs) has been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA. 2018 12;320(22):2354-2364). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating 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). Based on the majority of available evidence to date, this variant is likely to be 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 | Dec 02, 2018 | This sequence change results in a premature translational stop signal in the TTN gene (p.Lys2186Cysfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with dilated cardiomyopathy in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 130679). 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). 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. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at