ClinVar Miner

Submissions for variant NM_001256850.1(TTN):c.83086+5G>A (rs148231754)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184394 SCV000237019 likely pathogenic not provided 2016-02-05 criteria provided, single submitter clinical testing Although the c.83086+5 G>A likely pathogenic variant has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge, this variant destroys the canonical splice donor site in intron 279 and is predicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.83086+5 G>A is located in the A band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, the c.83086+5 G>A variant was not observed with any significance frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or the 1000 Genomes Project.
Invitae RCV000231587 SCV000286889 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-03-23 criteria provided, single submitter clinical testing This variant affects a highly conserved nucleotide within the consensus splice site of intron 329. The majority of introns (75%-85%) have a G at this position (PMID: 9536098). It is also located in the A-band of TTN. This variant is present in population databases (rs148231754, ExAC 0.01%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202525). 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 located in the A-band of TTN that has an uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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