ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13220G>A (p.Ser4407Asn)

gnomAD frequency: 0.00001  dbSNP: rs755585430
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621019 SCV000736149 uncertain significance Cardiovascular phenotype 2017-12-07 criteria provided, single submitter clinical testing The p.S4407N variant (also known as c.13220G>A), located in coding exon 90 of the RYR2 gene, results from a G to A substitution at nucleotide position 13220. The serine at codon 4407 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and asparagine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000772659 SCV000905918 uncertain significance Cardiomyopathy 2022-11-15 criteria provided, single submitter clinical testing This missense variant replaces serine with asparagine at codon 4407 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina RCV001101827 SCV001258468 uncertain significance Arrhythmogenic right ventricular dysplasia 2 2018-01-13 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 RCV001101828 SCV001258469 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2018-01-13 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001101828 SCV003275575 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-12-31 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002654 SCV004824184 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces serine with asparagine at codon 4407 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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