ClinVar Miner

Submissions for variant NM_133378.4(TTN):c.47728+5G>C (rs754717390)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184239 SCV000236861 pathogenic not provided 2014-05-12 criteria provided, single submitter clinical testing c.50509+5 G>C: IVS236+5 G>C in intron 236 of the TTN gene (NM_001256850.1). Although the c.50509+5 G>C mutation in the TTN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 236 and is predicted to cause abnormal gene splicing. Other splice site mutations in the TTN gene have been reported in association with cardiomyopathy. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.50509+5 G>C is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012).In summary, c.50509+5 G>C in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000331273 SCV000422755 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000385626 SCV000422756 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000295999 SCV000422757 uncertain significance Hereditary myopathy with early respiratory failure 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000350933 SCV000422758 uncertain significance Distal myopathy Markesbery-Griggs type 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000405475 SCV000422759 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000278169 SCV000422760 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000546209 SCV000643381 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-05-03 criteria provided, single submitter clinical testing This sequence change falls in intron 286, coding for the A-band of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs754717390, ExAC 0.002%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202391). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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