Submissions for variant NM_001035.3(RYR2):c.12331A>C (p.Asn4111His)

gnomAD frequency: 0.00002  dbSNP: rs192890834

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774039	SCV000907739	uncertain significance	Cardiomyopathy	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 4111 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/248462 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.
Invitae	RCV002534110	SCV003299050	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317362	SCV004020766	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.12331A>C (p.Asn4111His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12331A>C has been reported in the literature in individuals affected with LQTS, Cardiopulmonary arrest and ventricular fibrillation (Miyata_2018, Kawata_2016). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27452199, 29434162). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.