ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.506G>A (p.Arg169Gln) (rs397516539)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621755 SCV000737675 likely pathogenic Cardiovascular phenotype 2016-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000182658 SCV000235036 pathogenic not provided 2014-12-12 criteria provided, single submitter clinical testing p.Arg169Gln (CGA>CAA):c.506 G>A in exon 8 of the RYR2 gene (NM_001035.2). The Arg169Gln mutation in the RYR2 gene has been reported previously in an 18 year old female with exercised induced ventricular tachycardia and was absent from 100 reference alleles (Hsueh C et al., 2006). In addition, the NHLBI ESP Exome Variant Server reports Arg169Gln 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. Arg169Gln resides in the N-terminal domain, one of three mutation hot spots, in the RYR2 gene (Medeiros-Domingo A et al., 2009). Structural studies indicate that Arg169Gln leads to destabilization of the beta8-beta9 loop in this region of the protein (Lobo P et al., 2009). Mutations in nearby codons (Pro164Ser, Arg176Gln) have been reported in association with polymorphic ventricular tachycardia and ARVD further supporting the functional importance of this region of the protein. In summary, Arg169Gln in the RYR2 gene is interpreted as a disease-causing mutation. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced release of catecholamines causes a dysfunction of the calcium-ion channel in the myocytes (De La Fuente et al., 2008; Napolitano C et al., 2012; Priori S et al., 2002). CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Less commonly, CPVT is caused by autosomal recessive mutations in the CASQ2 gene (Napolitano C et al., 2012). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CPVT panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036762 SCV000060417 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2013-08-27 criteria provided, single submitter clinical testing The Arg169Gln variant in RYR2 has been reported in 3 Asian individuals with CPVT , was reported to occur de novo in one of these individuals, and was absent from 200 control chromosomes (Hsueh 2006, Ge 2012, Kawamura 2013). This variant has been identified by our laboratory in 1 Caucasian individual with LVNC and bidire ctional VT, and was not identified in large population studies. Arginine (Arg) a t position 169 is highly conserved in mammals and across evolutionarily distant species and computational analyses (AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg169Gln variant may impact the protein, which raises the possibility that a change at this position might not be tolerated. Additionally, this variant is located in a conserved domain of the RYR2 protein that may be critical for prot ein interactions and where other variants are clustered (Amador 2009, Lobo 2009) . In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.

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