ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1092A>C (p.Gln364His)

gnomAD frequency: 0.00003  dbSNP: rs763183698
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001183892 SCV001349738 uncertain significance Cardiomyopathy 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces glutamine with histidine at codon 364 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 2/279934 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001509123 SCV001715663 uncertain significance not provided 2019-12-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002559852 SCV002196215 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 364 of the RYR2 protein (p.Gln364His). This variant is present in population databases (rs763183698, gnomAD 0.003%). 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: 923317). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. 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.
Ambry Genetics RCV003293947 SCV003999086 uncertain significance Cardiovascular phenotype 2023-04-17 criteria provided, single submitter clinical testing The p.Q364H variant (also known as c.1092A>C), located in coding exon 13 of the RYR2 gene, results from an A to C substitution at nucleotide position 1092. The glutamine at codon 364 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004008418 SCV004846669 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces glutamine with histidine at codon 364 of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/279934 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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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