rs763098227
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBP6
The NM_001267550.2(TTN):โc.34663_34665delโ(p.Glu11555del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000411 in 1,597,886 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: ๐ 0.00026 ( 0 hom., cov: 32)
Exomes ๐: 0.00043 ( 1 hom. )
Consequence
TTN
NM_001267550.2 inframe_deletion
NM_001267550.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.93
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]
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 0 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
BP6
?
Variant 2-178674356-GTTC-G is Benign according to our data. Variant chr2-178674356-GTTC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284097.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.34663_34665del | p.Glu11555del | inframe_deletion | 151/363 | ENST00000589042.5 | |
LOC124906100 | XR_007087318.1 | n.2185+29860_2185+29862del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.34663_34665del | p.Glu11555del | inframe_deletion | 151/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-60143_503-60141del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000257 AC: 39AN: 151610Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000140 AC: 33AN: 236262Hom.: 0 AF XY: 0.000125 AC XY: 16AN XY: 127668
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GnomAD4 exome AF: 0.000427 AC: 618AN: 1446158Hom.: 1 AF XY: 0.000420 AC XY: 302AN XY: 718366
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GnomAD4 genome ? AF: 0.000257 AC: 39AN: 151728Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74156
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 16, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2019 | In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not located in the A-band nor the M-line region of titin, where the majority of pathogenic truncating variants have been reported; Identified in a patient with hypertrophic cardiomyopathy in published literature (Sanchez et al., 2016); This variant is associated with the following publications: (PMID: 27930701) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 24, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | TTN: BP4 - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2017 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 06, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 30, 2021 | Variant summary: TTN c.30760_30762delGAA (p.Glu10254del) results in an in-frame deletion that is predicted to remove one amino acid from I-band domain of the encoded protein. The variant allele was found at a frequency of 0.00026 in 151610 control chromosomes, predominantly at a frequency of 0.0005 within the Non-Finnish European subpopulation in the gnomAD database (gnomAD v3). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.30760_30762delGAA has been reported in the literature in one individual affected with Hypertrophy Cardiomyopathy and one individual who was tested for Cardiomyopathy panel and without specified phenotype (Sanchez_2016, Fedida_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at