ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.583+5G>A

gnomAD frequency: 0.00001  dbSNP: rs397517663
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000040502 SCV000064193 uncertain significance not specified 2014-07-23 criteria provided, single submitter clinical testing The 583+5G>A variant in TTN has been identified by our laboratory in 1 Black ind ividual with LVNC. It was absent from large population studies. This variant is located in the 5' splice region. Computational tools suggest a possible impact t o splicing; however, this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the 583+5G>A variant is unce rtain.
GeneDx RCV001573352 SCV000727069 likely benign not provided 2019-02-22 criteria provided, single submitter clinical testing
Invitae RCV000642802 SCV000764489 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2021-09-15 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 47232). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000040502 SCV001159937 uncertain significance not specified 2018-10-01 criteria provided, single submitter clinical testing The TTN c.583+5G>A variant (rs397517663), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 47232). This variant is found on three chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice donor site, though mRNA studies would be required to confirm an effect on splicing. Given the lack of clinical and functional data, the significance of the c.583+5G>A variant is uncertain at this time.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001573352 SCV001799111 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001573352 SCV001954555 likely benign not provided no assertion criteria provided clinical testing

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