Submissions for variant NM_001035.3(RYR2):c.14288A>G (p.Asn4763Ser)

dbSNP: rs794728803

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000182844	SCV001147787	likely pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV002517804	SCV001531486	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 4763 of the RYR2 protein (p.Asn4763Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia and/or sudden cardiac death (PMID: 29453246, 29915097, 31535183; Invitae). ClinVar contains an entry for this variant (Variation ID: 201356). 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 expected to disrupt RYR2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798636	SCV002042900	likely pathogenic	Cardiomyopathy	2019-08-13	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182844	SCV000280448	likely pathogenic	not provided	2013-10-13	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asn4763Ser (N4763S; c.14288 A>G) in RYR2 As of October 2013, p.Asn4763Ser has still not been reported in the literature either in association with CPVT nor in controls. However, the Familion laboratory reported to us that they have seen this variant in two unrelated probands sequenced there for CPVT. What’s more, in both cases this variant was de novo. This is a chemically conservative amino acid change, resulting in the replacement of a polar Asparagine with a polar Serine residue. The Asparagine at codon 4763 is absolutely conserved across 9 vertebrate species examined, as are the surrounding residues. In silico analysis with Polyphen-2 predicts the variant to be “probably damaging” with a score of 0.997. Changes at nearby residues have been reported in association with CPVT, including p.His4762Pro and p.Val4771Ile, supporting the functional importance of this region of the protein. Furthermore, residue 4673 falls within one of the 3 mutation “hotspots” for CPVT (the third “hotspot”, which is in the channel region between residues 3778-4959.) In total this variant has not been seen in >6200 controls and individuals from publicly available population datasets. No variation at this residue is found in the NHLBI Exome Sequncing Project dataset, which currently includes variant calls on some 4100 Caucasian and 1900 African American individuals. There is no variation at this residue in 1000 Genomes or dpSNP. GeneDx reports that it did not find the variant in up to 200 control individuals of Caucasian and African American descent.