rs754236839
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_001267550.2(TTN):c.34402_34416delACAGAGAAGAAAGTG(p.Thr11468_Val11472del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000224 in 1,607,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
TTN
NM_001267550.2 conservative_inframe_deletion
NM_001267550.2 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.42
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]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_001267550.2.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.34402_34416delACAGAGAAGAAAGTG | p.Thr11468_Val11472del | conservative_inframe_deletion | Exon 148 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.34402_34416delACAGAGAAGAAAGTG | p.Thr11468_Val11472del | conservative_inframe_deletion | Exon 148 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.0000198 AC: 3AN: 151794Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000541 AC: 13AN: 240490Hom.: 0 AF XY: 0.0000308 AC XY: 4AN XY: 130032
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GnomAD4 exome AF: 0.0000227 AC: 33AN: 1455654Hom.: 0 AF XY: 0.0000180 AC XY: 13AN XY: 723430
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GnomAD4 genome 0.0000198 AC: 3AN: 151794Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74120
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Sep 13, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jul 21, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In-frame deletion of five amino acids in a non-repeat region; Located in a region of TTN within the I-band (Deo et al., 2016; Schafer et al., 2017); In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Nov 08, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Cardiomyopathy Uncertain:1
Nov 17, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at