Submissions for variant NM_001035.3(RYR2):c.1548T>C (p.Asp516=) (rs146129084)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000036706	SCV000060361	likely benign	not specified	2015-03-06	criteria provided, single submitter	clinical testing	p.Asp516Asp in exon 16 of RYR2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (51/66652) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs146129084).
GeneDx	RCV000036706	SCV000171405	benign	not specified	2014-05-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000468470	SCV000554621	likely benign	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618567	SCV000736840	likely benign	Cardiovascular phenotype	2017-05-31	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign,In silico models in agreement (benign)
Color	RCV000771845	SCV000904559	benign	Cardiomyopathy	2018-10-15	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000036706	SCV000918168	benign	not specified	2018-10-22	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.1548T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00045 in 276574 control chromosomes (gnomAD). The observed variant frequency is approximately 7.5-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 benign. To our knowledge, no occurrence of c.1548T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.