Submissions for variant NM_001035.3(RYR2):c.13566C>T (p.Val4522=)

gnomAD frequency: 0.00366  dbSNP: rs57360419

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036680	SCV000060335	benign	not specified	2012-04-18	criteria provided, single submitter	clinical testing	Val4522Val in Exon 94 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and it has been identified in 1.0% (31/3128) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs57360419).
Invitae	RCV002513405	SCV000285699	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243868	SCV000319121	benign	Cardiovascular phenotype	2015-07-28	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588704	SCV000697608	benign	not provided	2017-03-13	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.13566C>T (p.Val4522Val) 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. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 85/38144 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.02059 (81/3934). This frequency is about 374 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/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000777799	SCV000913791	benign	Cardiomyopathy	2018-04-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588704	SCV001474235	likely benign	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036680	SCV001919107	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036680	SCV001931765	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036680	SCV001965867	benign	not specified		no assertion criteria provided	clinical testing