Submissions for variant NM_001035.3(RYR2):c.616G>A (p.Ala206Thr)

gnomAD frequency: 0.00001  dbSNP: rs930769080

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780692	SCV000918167	uncertain significance	not specified	2018-10-15	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.616G>A (p.Ala206Thr) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor and MIR motif of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246114 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.616G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001190795	SCV001358379	uncertain significance	Cardiomyopathy	2019-05-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 206 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 not been identified 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.
Invitae	RCV002535679	SCV001381246	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 206 of the RYR2 protein (p.Ala206Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 632974). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. 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.
GeneDx	RCV001775997	SCV002013822	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 632974; ClinVar); Has not been previously published as pathogenic or benign to our knowledge