ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14876G>A (p.Arg4959Gln) (rs794728811)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182854 SCV000235242 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing The R4959Q variant in the RYR2 gene has been previously reported in association with CPVT (Laitinen PJ et al., 2003, Allouis M et al., 2005, Tester DJ et al., 2005). R4959Q was initially identified in a 60 year-old female who experienced two episodes of syncope at age 40 (Laitinen PJ et al., 2003). The R4959Q variant was subsequently identified in multiple individuals diagnosed with CPVT, including ten symptomatic relatives that exhibited typical CPVT-related arrhythmia (Allouis M et al., 2005, Tester DJ et al., 2005). Considering all publications, R4959Q was absent from 668 control individuals (Laitinen PJ et al., 2003, Allouis M et al., 2005, Tester DJ et al., 2005), and it was not observed in approximately 6000 individuals of the NHLBI Exome Sequencing Project, indicating that it is not a benign polymorphism in these populations. R4959Q results in a semi-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a residue that is highly conserved across species. In silico analysis predicts R4959Q is probably damaging to the protein structure/function (Adzhubei IA et al., 2010). Other variants in the C-terminus of the RYR2 gene (E4950K) have been reported in association with CPVT, supporting the functional importance of this region of the protein. In summary, R4959Q in the RYR2 gene is interpreted as a disease-causing variant
Institute of Molecular Biology and Genetics,Federal Almazov North-West Medical Research Centre RCV000445354 SCV000494584 pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2016-07-27 criteria provided, single submitter research The patient was diagnosed with typical polymorphic ventricular tachycardia at the age of 12 followed by ICD implantation. No relatives are available for genetic testing.
SIB Swiss Institute of Bioinformatics RCV000445354 SCV000803500 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Ventricular tachycardia, catecholaminergic polymorphic, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:14571276,16188589,27231019,15721128). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:15721128).
Invitae RCV000702313 SCV000831162 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 4959 of the RYR2 protein (p.Arg4959Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with catecholaminergic polymorphic ventriculartachycardia in large multigenerational family, and has been also found in several individuals affected with RYR2-related disease (PMID: 14571276, 15721128, 16188589, 29453246). ClinVar contains an entry for this variant (Variation ID: 201365). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000182854 SCV001247133 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198530 SCV001369496 pathogenic mitochondrial 2019-06-28 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP4. This variant was detected in heterozygous state.

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