Submissions for variant NM_001035.3(RYR2):c.7160C>T (p.Ala2387Val)

dbSNP: rs794728754

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182758	SCV000235143	likely pathogenic	not provided	2018-12-07	criteria provided, single submitter	clinical testing	The A2387V variant that is likely pathogenic was identified in the RYR2 gene. This variant has previously been published in association with CPVT (Haugaa et al., 2010; Kawamura et al., 2013). In addition, this variant has been observed in one other unrelated individual referred for arrhythmia genetic testing at GeneDx. The A2387V variant was absent from 400 Japanese control alleles (Kawamura et al., 2013) and was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants affecting the same residue (A2387P, A2387T) and nearby residues (N2386I, Y2392C, A2394G) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the A2387V variant is located in the central domain, one of the three hot-spot regions of the RYR2 gene where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). However, the A2387V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the A2387V variant.Therefore, this variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002272163	SCV000937964	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala2387 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16188589, 19398665, 28237968, 28600387). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 201277). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 20106799, 23595086, 28237968). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2387 of the RYR2 protein (p.Ala2387Val).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272163	SCV002557360	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Changes to proline and threonine have also been regarded as likely pathogenic and pathogenic and reported in multiple individuals with catecholaminergic polymorphic ventricular tachycardia (ClinVar, LOVD, PMIDs: 29453246, 28237968, 29434162, 27538377, 22221940). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with catecholaminergic polymorphic ventricular tachycardia (ClinVar, PMIDs: 20106799, 29434162, 23595086, 28237968). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002372117	SCV002665851	likely pathogenic	Cardiovascular phenotype	2022-04-12	criteria provided, single submitter	clinical testing	The p.A2387V variant (also known as c.7160C>T), located in coding exon 47 of the RYR2 gene, results from a C to T substitution at nucleotide position 7160. The alanine at codon 2387 is replaced by valine, an amino acid with similar properties. This alteration has been identified in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Haugaa KH et al. Europace, 2010 Mar;12:417-23; Kawamura M et al. Circ. J., 2013 Apr;77:1705-13; Miyata K et al. Intern. Med., 2018 Jul;57:1813-1817; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424) and in a sudden cardiac death cohort (Broendberg AK et al. Heart, 2017 06;103:901-909). Another alteration at the same codon, p.A2387T (c.7159G>A), has been described in a CPVT cohort (Hayashi M et al. Circulation, 2009 May;119:2426-34). The p.A2387V variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV001535748	SCV001749871	not provided	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.