Submissions for variant NM_001035.3(RYR2):c.9666C>T (p.Ala3222=)

gnomAD frequency: 0.00308  dbSNP: rs116442127

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151769	SCV000200184	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Ala3222Ala in Exon 68 of RYR2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 1.0% (34/3260) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs116442127).
Invitae	RCV001093834	SCV000285754	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000375760	SCV000356389	likely benign	Arrhythmogenic right ventricular dysplasia 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001093834	SCV000356390	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587126	SCV000697636	benign	not provided	2016-08-22	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.9666C>T (p.Ala3222Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 108/120666 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0100082 (98/9792). This frequency is about 182 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Ambry Genetics	RCV000621133	SCV000736186	benign	Cardiovascular phenotype	2015-08-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768782	SCV000900152	benign	Cardiomyopathy	2016-06-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768782	SCV001342773	benign	Cardiomyopathy	2018-10-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587126	SCV001473778	benign	not provided	2019-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000587126	SCV001941479	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000151769	SCV001932857	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000151769	SCV001971047	benign	not specified		no assertion criteria provided	clinical testing