ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13957-5C>G (rs189772599)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000391467 SCV000356481 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297957 SCV000356482 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586624 SCV000697610 uncertain significance not provided 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.13957-5C>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/88482 control chromosomes at a frequency of 0.0000339, which approximately equals the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), suggesting this variant is likely a benign polymorphism. However, the small number of carriers in this population is too small to unequivocally classify this variant as benign. One clinical diagnostic laboratory/reputable database has classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as a VUS - possibly benign variant.
Invitae RCV000391467 SCV000941435 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-08 criteria provided, single submitter clinical testing This sequence change falls in intron 96 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein. This variant is present in population databases (rs189772599, ExAC 0.04%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 296765). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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