ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13600C>T (p.Pro4534Ser) (rs199624074)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171688 SCV000050707 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171688 SCV000235226 uncertain significance not provided 2015-10-30 criteria provided, single submitter clinical testing p.Pro4534Ser (CCC>TCC): c.13600 C>T in exon 94 of the RYR2 gene (NM_001035.2). The Pro4534Ser variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro4534Ser was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Pro4534Ser results in a non-conservative amino acid substitution of a non-polar Proline with a polar Serine at a position that is not well conserved across species, but is located in one of three mutation hot spot regions in the RYR2 gene (Medeiros- Domingo A et al., 2009). Nevertheless, in-silico analysis programs predict Pro4534Ser is benign to the protein structure/function. We cannot definitively determine if Pro4534Ser is a disease-causing mutation or a rare benign variant. The variant is found in POSTMORTEM panel(s).
Invitae RCV001067039 SCV001232068 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-12 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 4534 of the RYR2 protein (p.Pro4534Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs199624074, ExAC 0.03%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 191491). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV001185803 SCV001352107 uncertain significance Cardiomyopathy 2018-12-17 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000212984 SCV000280445 uncertain significance not specified 2015-06-01 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro4534Ser (c.13600C>T) in the RYR2 gene (NM_001035) Given the lack of case data and lack of ancestry-matched controls, we consider this variant a variant of uncertain significance. I could find no report of the variant in association with disease. It is not listed in ClinVar (as of July 8th, 2014). Per Ng et al (2013) it is not listed in HGMD or any LSDB they checked. In silico analysis with PolyPhen-2 predicts the variant to be benign. The proline at codon 4534 is conserved across species. In total the variant has been seen in 1 of 7009 individuals from publicly available population datasets. There is no variation at codon 4534 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 8th, 2014). The variant was seen in 1 of 509 individuals in the ClinSeq project (Ng et al 2013), a sample not selected for arrhythmia or family history of sudden death (3.7% were Hispanic). Note that this dataset does not match the patient's ancestry (Hispanic). The variant is listed in dbSNP with the only submission being the ClinSeq data (rs199624074).

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