Submissions for variant NM_001035.3(RYR2):c.13957-5C>G

gnomAD frequency: 0.00010  dbSNP: rs189772599

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000391467	SCV000356481	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000297957	SCV000356482	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586624	SCV000697610	uncertain significance	not provided	2017-03-20	criteria provided, single submitter	clinical testing	Variant summary: The RYR2 c.13957-5C>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign 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 3/88482 control chromosomes at a frequency of 0.0000339, which approximately equals the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), suggesting this variant is likely a benign polymorphism. However, the small number of carriers in this population is too small to unequivocally classify this variant as benign. One clinical diagnostic laboratory/reputable database has classified this variant as uncertain significance. 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 a VUS - possibly benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002520480	SCV000941435	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392830	SCV002701673	uncertain significance	Cardiovascular phenotype	2023-10-04	criteria provided, single submitter	clinical testing	The c.13957-5C>G intronic variant results from a C to G substitution 5 nucleotides upstream from coding exon 97 in the RYR2 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000391467	SCV004829520	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2023-12-01	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the -5 position of intron 96 of the RYR2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 10/271500 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.