Submissions for variant NM_001035.3(RYR2):c.6504C>G (p.His2168Gln) (rs760237464)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430239	SCV000520772	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene. The H2168Q variant has been published in two patients with CPVT (Medeiros-Domingo et al., 2009); however, additional clinical information and functional studies were not included. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H2168Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis suggests that this variant is probably damaging to the protein structure/function. Nevertheless, the H2168Q 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).
Invitae	RCV001047289	SCV001211235	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2019-04-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with glutamine at codon 2168 of the RYR2 protein (p.His2168Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). ClinVar contains an entry for this variant (Variation ID: 381484). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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