rs375735354
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.3514C>A(p.Leu1172Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000595 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
5
11
Clinical Significance
Conservation
PhyloP100: 4.06
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 Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, TTN
BP4
?
Computational evidence support a benign effect (MetaRNN=0.28133482).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.3514C>A | p.Leu1172Ile | missense_variant | 21/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.3514C>A | p.Leu1172Ile | missense_variant | 21/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.3514C>A | p.Leu1172Ile | missense_variant | 21/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.3514C>A | p.Leu1172Ile | missense_variant | 21/46 | 5 | NM_133379.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250974Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135626
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GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461654Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 727128
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 30, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 14, 2014 | The Leu1172Ile variant in TTN has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 1/8600 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Leu1172Ile variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 22, 2023 | Variant summary: TTN c.3514C>A (p.Leu1172Ile) results in a conservative amino acid change located in the Z-disk region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250974 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3514C>A has been reported in the literature in at least one individual affected with childhood onset myopathy attributed to pathogenic variants in the NEB gene (e.g., Scoto_2013). This report does not provide unequivocal conclusions about association of the variant with TTN-related conditions. The co-occurrence with other recessively inherited pathogenic variant(s) mentioned above (NEB c.24372_24375dup, p.Val8126fs; NEB, exon 55 deletion, p.Arg2478_Asp2512del), provide supporting evidence for a benign role due to an alternative molecular basis of disease (Scoto_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23443021). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 04, 2019 | The p.L1126I variant (also known as c.3376C>A), located in coding exon 19 of the TTN gene, results from a C to A substitution at nucleotide position 3376. The leucine at codon 1126 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;.;N;N;.;N
REVEL
Benign
Sift
Benign
T;T;.;.;T;T;.;T
Polyphen
0.99, 1.0
.;.;.;D;.;.;D;D
Vest4
MVP
MPC
0.38
ClinPred
T
GERP RS
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