ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10024G>C (p.Ala3342Pro)

dbSNP: rs779445295
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182884 SCV000235272 uncertain significance not provided 2017-08-17 criteria provided, single submitter clinical testing This variant is denoted Ala3342Pro (aka A3342P) at the protein level and c.10024 G>C at the cDNA level. The Ala3342Pro variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ala3342Pro results in a conservative amino acid substitution of one non-polar amino acid for another at a position that is not well conserved across species throughout evolution. In addition, no mutations in nearby residues have been reported in association with CPVT, indicating this region of the protein may be tolerant of change. However, according to the NHLBI ESP Exome Variant Server, Ala3342Pro was not observed in approximately 4,500 individuals from European and African American backgrounds, indicating that it is not a common sequence variant in these populations. In summary, the clinical significance of the Ala3342Pro variant is unclear at this time. The variant is found in CPVT panel(s).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256910 SCV001433424 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2019-08-29 criteria provided, single submitter clinical testing
Invitae RCV001256910 SCV003524139 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-09-03 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 201394). This missense change has been observed in individual(s) with idiopathic cardiac arrest (PMID: 28600387). This variant is present in population databases (rs779445295, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3342 of the RYR2 protein (p.Ala3342Pro).

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