Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.95415C>A(p.Phe31805Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,612,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
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
GeneDx
Aug 04, 2022
Identified in unrelated patients with DCM, ARVC and unspecified skeletal myopathy in published literature (Campuzano et al. 2015; Forleo et al., 2017l Savarese et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.87711C>A p.(F29237) and c.68220 C>A p.(F22740L) due to use of alternate nomenclature/transcripts; This variant is associated with the following publications: (PMID: 34426522, 32039858, 24636144, 28750076, 26516846) -
Uncertain significance, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Jan 09, 2023
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not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jul 19, 2022
Variant summary: TTN c.87711C>A (p.Phe29237Leu) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 248118 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4e-05 vs 0.00039), allowing no conclusion about variant significance. c.87711C>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy and ARVC (Campuzano_2015, Forleo_2017). These report(s) 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. Five 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
Invitae
Dec 19, 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
Mar 14, 2019
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Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter
Uncertain significance, criteria provided, single submitter
clinical testing
Blueprint Genetics
Oct 06, 2015
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Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 25, 2020
The p.F22740L variant (also known as c.68220C>A), located in coding exon 170 of the TTN gene, results from a C to A substitution at nucleotide position 68220. The phenylalanine at codon 22740 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in an individual with arrhythmogenic right ventricular cardiomyopathy who also had variants in the OBSCN gene (Forleo C et al. PLoS ONE, 2017 Jul;12:e0181842). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -