Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP2BP6_Very_Strong
The NM_001267550.2(TTN):c.105787_105788delinsTT(p.Ala35263Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35263S) has been classified as Likely benign.
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 -5 ACMG points.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
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
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 2-178530827-GC-AA is Benign according to our data. Variant chr2-178530827-GC-AA is described in ClinVar as [Likely_benign]. Clinvar id is 202340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
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Benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Aug 26, 2019
Variant summary: TTN c.98083_98084delinsTT (p.Ala32695Phe) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 280436 control chromosomes in the gnomAD database, including 25 homozygotes. The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.98083_98084delinsTT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 31, 2024
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Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Jan 12, 2023
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Early-onset myopathy with fatal cardiomyopathy Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Sep 26, 2012
The variant is found in DCM panel(s). -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 28, 2012
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -