ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9625C>A (p.Pro3209Thr) (rs767375014)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182779 SCV000235165 uncertain significance not provided 2012-12-03 criteria provided, single submitter clinical testing p.Pro3209Thr (P3209T) CCG>ACG: c.9625 C>A in exon 68 of the RYR2 gene (NM_001035.2). The P3209T variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. P3209T results in a non-conservative amino acid substitution of sterically-constrained, non-polar Proline residue with a neutral, polar Threonine residue at a position that is conserved across species. The NHLBI ESP Exome Variant Server reports P3209T was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, there have been no mutations reported near P3209T, indicating this region of the protein may be tolerant of change. We cannot definitively determine if P3209T is a disease-causing mutation or a rare benign variant. The variant is found in CPVT panel(s).
Invitae RCV001041232 SCV001204834 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 3209 of the RYR2 protein (p.Pro3209Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs767375014, ExAC 0.002%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201296). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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