ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12752A>G (p.Asn4251Ser)

gnomAD frequency: 0.00001  dbSNP: rs750064223
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001757409 SCV002007579 uncertain significance not provided 2019-11-21 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009)
Labcorp Genetics (formerly Invitae), Labcorp RCV002544167 SCV003446040 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2023-08-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004009032 SCV004822954 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 4251 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 been identified in 4/247540 chromosomes 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.
Clinical Genomics Laboratory, Stanford Medicine RCV002544167 SCV005051690 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2021-07-21 criteria provided, single submitter clinical testing The p.Asn4251Ser variant in the RYR2 gene has not been previously reported in association with disease. This variant has been identified in 4/34,416 Latino/Admixed American chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been observed in the general population, it has not been observed at a high enough frequency to rule out pathogenicity. The p.Asn4251Ser variant occurs in exon 90 of RYR2, an exon which has been shown to be enriched for pathogenic variants and partially overlaps with a hot-spot region of the RyR2 protein (Medeiros-Domingo et al., 2009; Kapplinger et al., 2018; Guo et al., 2021). The asparagine at position 4251is highly evolutionarily conserved. Computational tools do not predict that the p.Asn4251Ser variant impacts protein function; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Asn4251Servariant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: None]

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