Submissions for variant NM_001035.3(RYR2):c.5261G>C (p.Ser1754Thr)

gnomAD frequency: 0.00001  dbSNP: rs397516542

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036765	SCV000060420	uncertain significance	not specified	2014-05-22	criteria provided, single submitter	clinical testing	The Ser1754Thr variant in RYR2 has not been previously reported in any other fam ilies with cardiomyopathy or in large population studies. Computational predicti on tools and conservation analysis do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the c linical significance of the Ser1754Thr variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513431	SCV001230496	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1754 of the RYR2 protein (p.Ser1754Thr). This variant is present in population databases (rs397516542, gnomAD 0.009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257, 28416588). ClinVar contains an entry for this variant (Variation ID: 43804). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001189710	SCV001357060	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1754 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 been reported in two unrelated individuals affected with dilated cardiomyopathy (PMID: 28416588 and 24503780). This variant has been identified in 3/248968 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.
Fulgent Genetics, Fulgent Genetics	RCV002496574	SCV002812064	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2022-02-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528183	SCV004110251	uncertain significance	RYR2-related disorder	2023-03-29	criteria provided, single submitter	clinical testing	The RYR2 c.5261G>C variant is predicted to result in the amino acid substitution p.Ser1754Thr. This variant was reported in three individuals with dilated cardiomyopathy (Table S1, Pugh et al. 2014. PubMed ID: 24503780; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S1, Dal Ferro et al. 2017. PubMed ID: 28416588). However, in one of the individuals, additional variants including a pathogenic LMNA c.949G>A (p.Glu317Lys) were also identified (Table S1, Dal Ferro et al. 2017. PubMed ID: 28416588). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-237777689-G-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	RCV003996289	SCV004819484	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1754 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/248968 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV004589529	SCV005079914	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing	Identified in patients with DCM in published literature (PMID: 28416588, 27532257, 24503780); at least one patient harbored additional cardiogenetic variants; Not observed at significant frequency in large population cohorts (gnomAD); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19926015, 28416588, 27532257, 24503780)