ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10725+4A>T

gnomAD frequency: 0.00006  dbSNP: rs116444428
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769801 SCV000901227 uncertain significance Cardiomyopathy 2019-12-09 criteria provided, single submitter clinical testing
Invitae RCV001101643 SCV001230638 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-03 criteria provided, single submitter clinical testing This sequence change falls in intron 75 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs116444428, gnomAD 0.01%). 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: 626623). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Illumina Laboratory Services, Illumina RCV001101643 SCV001258268 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2018-01-19 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001101644 SCV001258269 uncertain significance Arrhythmogenic right ventricular dysplasia 2 2018-01-19 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health RCV000769801 SCV001360077 likely benign Cardiomyopathy 2018-11-16 criteria provided, single submitter clinical testing
GeneDx RCV002260667 SCV002540439 uncertain significance not provided 2022-06-21 criteria provided, single submitter clinical testing In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002422653 SCV002719031 uncertain significance Cardiovascular phenotype 2022-03-24 criteria provided, single submitter clinical testing The c.10725+4A>T variant results from an A to T substitution 4 nucleotides after coding exon 75 in the RYR2 gene. This nucleotide position is highly 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.

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