ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs397516542
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Total submissions: 5
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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.
Invitae RCV002513431 SCV001230496 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-06-05 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). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 43804). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257, 28416588). This variant is present in population databases (rs397516542, gnomAD 0.009%).
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 RCV003390728 SCV004110251 uncertain significance RYR2-related condition 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.

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