ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10230T>C (p.His3410=) (rs370078129)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586128 SCV000697598 uncertain significance not provided 2016-01-08 criteria provided, single submitter clinical testing Variant summary: This c.10230T>C variant affects a non-conserved nucleotide at the last nucleotide of exon 70, resulting in synonymous amino acid change. Due to location of this variant, it is suspected/predicated to affect normal splicing. In line with this notion, Mutation Taster predicts the variant to be disease-causing and ESEfinder predicts that it may affect the binding to ESEs. However, 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. These prediction results are not definitive and need to be confirmed by functional studies. This variant was found in 1/83064 chromosomes from large and broad populations from ExAC at a frequency of 0.000012, which does not exceed the maximal expected frequency of a pathogenic allele (0.000055) in this gene. To our knowledge, this variant has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, this variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics RCV000622170 SCV000736281 uncertain significance Cardiovascular phenotype 2016-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000794760 SCV000934187 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-01 criteria provided, single submitter clinical testing This sequence change affects codon 3410 of the RYR2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RYR2 protein. This variant is present in population databases (rs370078129, ExAC 0.002%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 496086). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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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