Submissions for variant NM_001035.3(RYR2):c.11965A>G (p.Asn3989Asp)

dbSNP: rs794728779

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182804	SCV000235190	pathogenic	not provided	2012-11-09	criteria provided, single submitter	clinical testing	p.Asn3989Asp (AAT>GAT):c.11965 A>G in exon 90 of the RYR2 gene (NM_001035.2). The Asn3989Asp mutation in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Asn3989Asp results in a non-conservative amino acid substitution of a neutral, polar Asparagine with a negatively charged Aspartic acid at a residue that is conserved across species. In silico analysis predicts Asn3989Asp is probably damaging to the protein structure/function. The Asn3989Asp mutation is located in the channel region mutation hot spot, where other mutations in nearby codons (Met3978Ile, Val3990Asp) have been reported in association with CPVT (Medeiros-Domingo A et al., 2009). In addition, the Asn3989Asp has been observed in other unrelated individuals at GeneDx. The NHLBI ESP Exome Variant Server reports Asn3989Asp was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, Asn3989Asp in the RYR2 gene is interpreted as a disease-causing mutation. The variant is found in POSTMORTEM,CPVT panel(s).
Invitae	RCV002515334	SCV001566818	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-03-19	criteria provided, single submitter	clinical testing	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. 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 C15"). This variant has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201319). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 3989 of the RYR2 protein (p.Asn3989Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid.