ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs765195072
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Total submissions: 3
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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 2019-10-23 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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