Submissions for variant NM_001035.3(RYR2):c.4585A>C (p.Thr1529Pro)

gnomAD frequency: 0.00001  dbSNP: rs765195072

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182724	SCV000235107	uncertain significance	not provided	2018-04-18	criteria provided, single submitter	clinical testing	The T1529P variant of uncertain significance in the RYR2 gene has not been published as pathogenic or been reported as benign to our knowledge. The T1529P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The T1529P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the T1529P variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).
Color Diagnostics, LLC DBA Color Health	RCV001190713	SCV001358289	uncertain significance	Cardiomyopathy	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 1529 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 2/244280 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.
Ambry Genetics	RCV002336455	SCV002637037	uncertain significance	Cardiovascular phenotype	2024-02-12	criteria provided, single submitter	clinical testing	The p.T1529P variant (also known as c.4585A>C), located in coding exon 34 of the RYR2 gene, results from an A to C substitution at nucleotide position 4585. The threonine at codon 1529 is replaced by proline, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	RCV003996757	SCV004818300	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 1529 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 2/244280 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.