Submissions for variant NM_001035.3(RYR2):c.4337T>C (p.Ile1446Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV004529797	SCV004110421	uncertain significance	RYR2-related disorder	2023-01-10	criteria provided, single submitter	clinical testing	The RYR2 c.4337T>C variant is predicted to result in the amino acid substitution p.Ile1446Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-237756837-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004011300	SCV004831192	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1446 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 RYR2-related disorders in the literature. This variant has been identified in 1/248990 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.