ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13267A>C (p.Lys4423Gln)

gnomAD frequency: 0.00010  dbSNP: rs376908332
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171687 SCV000055293 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Invitae RCV002516563 SCV000760616 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-22 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001179790 SCV001344567 uncertain significance Cardiomyopathy 2023-05-01 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamine at codon 4423 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 been reported in an individual affected with sudden death (PMID: 26272908). This variant has been identified in 5/243840 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.
GeneDx RCV000171687 SCV001771117 uncertain significance not provided 2023-07-21 criteria provided, single submitter clinical testing Reported in association with sudden infant death syndrome (SIDS) in the published literature (Santori et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense 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); This variant is associated with the following publications: (PMID: 26272908, 19926015, 28404607, 23861362)
Ambry Genetics RCV002381551 SCV002691581 uncertain significance Cardiovascular phenotype 2020-08-31 criteria provided, single submitter clinical testing The p.K4423Q variant (also known as c.13267A>C), located in coding exon 91 of the RYR2 gene, results from an A to C substitution at nucleotide position 13267. The lysine at codon 4423 is replaced by glutamine, an amino acid with similar properties. This alteration has been reported in a sudden cardiac death cohort (Santori M et al. Arch. Dis. Child., 2015 Oct;100:952-6). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is well conserved in available 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.

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