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

gnomAD frequency: 0.00001  dbSNP: rs397517663

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642802	SCV000764489	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-12	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. This variant is present in population databases (rs397517663, gnomAD 0.003%). 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 is not likely to affect RNA splicing. This variant is located in the Z band of TTN (PMID: 25589632). Non-truncating 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