Submissions for variant NM_001035.3(RYR2):c.9407G>A (p.Ser3136Asn)

gnomAD frequency: 0.00001  dbSNP: rs748194372

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171172	SCV000221368	uncertain significance	not provided	2019-07-27	criteria provided, single submitter	research	Updated local variant frequency is incompatible with the prior classification of this variant as likely pathogenic.
Invitae	RCV002516555	SCV001223615	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-01-24	criteria provided, single submitter	clinical testing	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: 190998). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs748194372, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 3136 of the RYR2 protein (p.Ser3136Asn).
Color Diagnostics, LLC DBA Color Health	RCV001180081	SCV001344935	uncertain significance	Cardiomyopathy	2019-10-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 3136 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248596 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.