rs761362832
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_001267550.2(TTN):c.99518G>A(p.Cys33173Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
9
5
3
Clinical Significance
Conservation
PhyloP100: 7.91
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.99518G>A | p.Cys33173Tyr | missense_variant | 355/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.99518G>A | p.Cys33173Tyr | missense_variant | 355/363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000522 AC: 13AN: 248920Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135038
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461474Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727010
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | TTN: PP3 - |
not provided, no classification provided | clinical testing | GeneDx | Jun 03, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 24, 2020 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 06, 2020 | The c.91814G>A sequence change results in an amino acid change, p.Cys30605Tyr. This sequence change has been described in the gnomAD database with a low population frequency of 0.005223% (dbSNP rs761362832). The p.Cys30605Tyr change affects a highly conserved amino acid residue located in a domain of the TTN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys30605Tyr substitution. This sequence change does not appear to have been previously described in patients with TTN-related disorders. Due to the lack of sufficient evidence, the clinical significance of the p.Cys30605Tyr change remains unknown at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2020 | Variant summary: TTN c.91814G>A (p.Cys30605Tyr) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 248920 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database (exomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00032 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.91814G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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 | Nov 08, 2017 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Dec 24, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;.;H;.;.;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
MutPred
0.78
.;.;.;Gain of phosphorylation at C31532 (P = 0.0869);.;.;Gain of phosphorylation at C31532 (P = 0.0869);
MVP
MPC
0.60
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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