Submissions for variant NM_001035.3(RYR2):c.684C>T (p.Leu228=)

gnomAD frequency: 0.00008  dbSNP: rs72549417

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036782	SCV000060437	likely benign	not specified	2012-08-03	criteria provided, single submitter	clinical testing	Leu228Leu in exon 10 of RYR2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. This variant has been listed in dbSNP without frequency information (dbSNP rs72549417). Leu228Leu in exon 10 of RYR2 (rs72549 417; allele frequency = n/a)
Illumina Laboratory Services, Illumina	RCV000265346	SCV000356195	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001093846	SCV000356196	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-12	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.
Invitae	RCV001093846	SCV000554613	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589666	SCV000697629	benign	not provided	2016-12-05	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.684C>T (p.Leu228Leu) variant causes a synonymous change involving a non-conserved nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 9/118872 (1/13208), predominantly in the East Asian cohort, 7/8564 (1/1223), which is about 15 times the estimated maximal expected allele frequency for a pathogenic RYR2 variant of 1/18181. Therefore, suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, one clinical diagnostic laboratory/reputable database has classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant has been classified as Benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768754	SCV000900124	likely benign	Cardiomyopathy	2017-08-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768754	SCV000903655	likely benign	Cardiomyopathy	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000589666	SCV001945103	likely benign	not provided	2019-12-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362626	SCV002666025	likely benign	Cardiovascular phenotype	2020-11-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CeGaT Center for Human Genetics Tuebingen	RCV000589666	SCV004126199	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	RYR2: BP4, BP7, BS1