Submissions for variant NM_001035.3(RYR2):c.7222-12dup

dbSNP: rs145140335

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036788	SCV000060443	likely benign	not specified	2012-08-14	criteria provided, single submitter	clinical testing	7222-12_7222-11insT in intron 47 of RYR2: This variant is not expected to have c linical significance because it is located outside the conserved splicing consen sus sequence.
GeneDx	RCV000036788	SCV000235007	benign	not specified	2014-04-30	criteria provided, single submitter	clinical testing	The variant is found in CARDIOMYOPATHY panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036788	SCV001362192	benign	not specified	2019-10-29	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.7222-12dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.0049 in 210328 control chromosomes, predominantly at a frequency of 0.047 within the African or African-American subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is significantly above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.7222-12dupT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736552	SCV004564756	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing