rs397517565
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001267550.2(TTN):c.41610del(p.Val13871SerfsTer7) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
TTN
NM_001267550.2 frameshift, splice_region
NM_001267550.2 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.43
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
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-178635713-CT-C is Pathogenic according to our data. Variant chr2-178635713-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46947.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr2-178635713-CT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.41610del | p.Val13871SerfsTer7 | frameshift_variant, splice_region_variant | 227/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.41610del | p.Val13871SerfsTer7 | frameshift_variant, splice_region_variant | 227/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+38034del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 16, 2011 | The Val11303fs variant (TTN) has not been previous reported but has been identif ied by our laboratory in 1 individual with DCM. This variant is predicted to cau se a frameshift, which alters the protein's amino acid sequence beginning at cod on 11303 and leads to a premature stop codon 7 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein (loss of funct ion). Loss of function variants in TTN are common in patients with DCM (Jon Seid man, pers. comm.). In summary, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2013 | c.36687delA: p.Val12230SerfsX7 (V12230SfsX7) in exon 177 of the TTN gene (NM_001256850.1). The normal sequence with the base that is deleted in braces is: tagA{A}GTCA, with intronic sequence in lowercase letters and exonic sequence in uppercase letters. The c.36687delA variant in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. This variant causes a shift in reading frame starting at codon Valine 12230, changing it to a Serine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Val12230SerfsX7. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012), and c.36687delA is not located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). With the clinical and molecular information available at this time, we cannot definitively determine if c.36687delA is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). - |
Computational scores
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Splicing
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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