Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.65782C>T(p.Arg21928Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000678 in 1,606,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21928Q) 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]
Uncertain significance, criteria provided, single submitter
clinical testing
Mayo Clinic Laboratories, Mayo Clinic
Aug 26, 2019
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Uncertain significance, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Apr 22, 2021
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Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jun 13, 2018
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Uncertain significance, criteria provided, single submitter
clinical testing
Athena Diagnostics
Jan 04, 2023
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Jul 07, 2015
The p.Arg19360Trp variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/9492 African chromosomes and 2/64022 European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs371856109). Computational prediction tools and c onservation analysis do not provide strong support for or against an impact to t he protein. In summary, the clinical significance of the p.Arg19360Trp variant i s uncertain. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jan 27, 2017
Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s). -
TTN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Dec 20, 2023
The TTN c.65782C>T variant is predicted to result in the amino acid substitution p.Arg21928Trp. This variant was reported in an individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Apr 11, 2017
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Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Sep 07, 2016
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Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
May 06, 2020
The p.R12863W variant (also known as c.38587C>T), located in coding exon 140 of the TTN gene, results from a C to T substitution at nucleotide position 38587. The arginine at codon 12863 is replaced by tryptophan, an amino acid with dissimilar 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. -