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

gnomAD frequency: 0.00001  dbSNP: rs767375014

Total submissions: 3

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	RCV002517798	SCV001204834	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3209 of the RYR2 protein (p.Pro3209Thr). This variant is present in population databases (rs767375014, 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: 201296). 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.
Color Diagnostics, LLC DBA Color Health	RCV001523855	SCV001733554	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This variant replaces proline with threonine at codon 3209 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 cardiovascular disorders in the literature. This variant has been identified in 2/249010 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.