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

gnomAD frequency: 0.00005  dbSNP: rs199624074

Total submissions: 7

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	RCV002516564	SCV001232068	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-06-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185803	SCV001352107	uncertain significance	Cardiomyopathy	2022-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 4534 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual afflicted with unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 11/237172 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.
Ambry Genetics	RCV002381552	SCV002698267	uncertain significance	Cardiovascular phenotype	2021-01-06	criteria provided, single submitter	clinical testing	The p.P4534S variant (also known as c.13600C>T), located in coding exon 94 of the RYR2 gene, results from a C to T substitution at nucleotide position 13600. The proline at codon 4534 is replaced by serine, an amino acid with similar properties. This variant was detected in an arrhythmia genetic testing case with limited clinical details provided (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration has been reported as a secondary cardiac variant in exome cohorts; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000171688	SCV004126224	uncertain significance	not provided	2023-01-01	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).