Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_001267550.2(TTN):c.915-4_915-3insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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]
Verdict is Likely_benign. Variant got -1 ACMG points.
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 2-178795255-G-GA is Benign according to our data. Variant chr2-178795255-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179060.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Mar 14, 2014
The 915-4_915-3insT variant in TTN has not been reported in individuals with car diomyopathy, but has been identified in 2/8254 European American chromosomes and 1/4266 African American chromosomes by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/). This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this informa tion is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the 915-4_915 -3insT variant. -