Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001267550.2(TTN):c.98465A>G(p.Asp32822Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32822N) has been classified as Uncertain significance.
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]
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
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PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, TTN
BP4
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BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.17714193).
BP6
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BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-178539600-T-C is Benign according to our data. Variant chr2-178539600-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165682.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=2}.
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 03, 2021
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Jun 21, 2023
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jun 21, 2018
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not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Apr 03, 2013
The Asp30254Gly variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has not been identified in larg e European American and African American populations by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/), though it may be present in othe r populations. Computational analyses (conservation, PolyPhen2, and SIFT) sugges t that this variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. Additional information is needed to ful ly assess the clinical significance of this variant. -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter
research
Genetics and Genomics Program, Sidra Medicine
-
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Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 28, 2018
The p.D23757G variant (also known as c.71270A>G), located in coding exon 179 of the TTN gene, results from an A to G substitution at nucleotide position 71270. The aspartic acid at codon 23757 is replaced by glycine, an amino acid with 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. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 26, 2024
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Cardiomyopathy Benign:1
Benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario