Submissions for variant NM_001035.3(RYR2):c.8162T>C (p.Ile2721Thr)

gnomAD frequency: 0.00069  dbSNP: rs201500134

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036794	SCV000060449	uncertain significance	not specified	2012-09-21	criteria provided, single submitter	clinical testing	The Ile2721Thr variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 4/7968 E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. Additional inform ation is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000036794	SCV000235152	uncertain significance	not specified	2016-09-28	criteria provided, single submitter	clinical testing	The I2721T variant of uncertain significance in the RYR2 gene has been previously reported intwo individuals (van Spaendonck-Zwarts et al., 2014; Hertz et al., 2015). This variant was initiallyreported as a variant of uncertain significance in one individual with atrial fibrillation and dilatedcardiomyopathy who was found to harbor additional variants of uncertain significance in theDMD and TTN genes (van Spaendonck-Zwarts et al., 2014). Subsequently, Hertz et al. (2015)reported I2721T in an individual diagnosed with Long QT syndrome at 19 years of age; however,she was also found to harbor a KCNH2 variant classified as likely pathogenic. This variant hasalso been identified independently and in conjunction with additional cardiogenetic variants inindividuals referred for arrhythmia and cardiomyopathy genetic testing at GeneDx; however, thusfar, segregation data is limited or absent for these individuals due to the lack of clinical informationprovided and/or insufficient participation by informative family members. Additionally, theI2721T variant is classified in ClinVar as a variant of uncertain significance by two clinicallaboratories (ClinVar SCV000060449.4; SCV000285751.1; Landrum et al., 2016). The I2721Tvariant was not observed with any significant frequency in approximately 5,800 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project. Although thissubstitution occurs at a position where amino acids with similar properties to Isoleucine aretolerated across species, the I2721T variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/orother properties. Consequently, in silico analysis predicts this variant is probably damaging to theprotein structure/function. Nevertheless, the I2721T variant is not located in one of the threehot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur(Medeiros-Domingo et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign.
Invitae	RCV001095885	SCV000285751	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000036794	SCV000605050	uncertain significance	not specified	2016-12-01	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000590879	SCV000700103	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics	RCV000621651	SCV000734924	likely benign	Cardiovascular phenotype	2023-07-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000771869	SCV000904592	likely benign	Cardiomyopathy	2018-12-20	criteria provided, single submitter	clinical testing	Likely Benign variant based on current evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome, who also carried a pathogenic truncation variant in the KCNH2 gene (PMID: 25467552). This variant has been identified in 97/163874 chromosomes (84/68536 non-Finnish European chromosomes, 0.1225%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the RYR2-related disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.
Illumina Laboratory Services, Illumina	RCV001095884	SCV001252061	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001095885	SCV001252062	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771869	SCV001332822	likely benign	Cardiomyopathy	2020-03-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036794	SCV001467924	likely benign	not specified	2020-12-29	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.8162T>C (p.Ile2721Thr) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 137452 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8162T>C has been reported in the literature in individuals affected with Arrhythmia, LQTS, catecholaminergic polymorphic ventricular tachycardia, sudden arrhythmic death syndrome and Wolff-Parkinson-White syndrome (vanSpaendonck_2014, Hertz_2014, Landstrom_2017, Munroe_2018, Raju_2019, Coban-Akdemir_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (TTN c.86171_86174dupAAAG, p.Asn28726Lysfs*3; LMNA c.725C>T, p.Ala242Val; KCNH2 c.1286del, p.A429Vfs*5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and likely benign (5x). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004541108	SCV004784326	likely benign	RYR2-related disorder	2022-01-31	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656198	SCV000678392	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000227013	SCV001740620	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000227013	SCV001922240	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000227013	SCV001929013	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000227013	SCV001956908	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000227013	SCV001975226	likely benign	not provided		no assertion criteria provided	clinical testing