Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and 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 | 2022-08-17 | criteria provided, single submitter | clinical testing | The c.10230T>C variant (also known as p.H3410H), located in coding exon 70 of the RYR2 gene, results from a T to C substitution at nucleotide position 10230. This nucleotide substitution does not change the at codon 3410. However, this change occurs in the last base pair of coding exon 70, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV002530909 | SCV000934187 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-12-11 | 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. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR2-related conditions. 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. 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. |