Submissions for variant NM_001035.3(RYR2):c.13276GAA[2] (p.Glu4428del)

dbSNP: rs869025516

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208370	SCV000264196	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000414609	SCV000491843	uncertain significance	not provided	2016-11-17	criteria provided, single submitter	clinical testing	The normal sequence with the bases that are deleted in brackets is: AGAA[delGAA]AAGG. A variant of uncertain significance has been identified in the RYR2 gene. The c.13282_13284delGAA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.13282_13284delGAA variant results in the deletion of a conserved Glutamic acid residue at codon 4428 in the RYR2 gene. However, as this is an in-frame deletion, it is not expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517406	SCV001198021	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-08-29	criteria provided, single submitter	clinical testing	This variant, c.13282_13284del, results in the deletion of 1 amino acid(s) of the RYR2 protein (p.Glu4428del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755465177, gnomAD 0.0009%). 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: 222798). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Color Diagnostics, LLC DBA Color Health	RCV001192094	SCV001360066	uncertain significance	Cardiomyopathy	2023-05-18	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 amino acid from the RYR2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/244200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Fulgent Genetics, Fulgent Genetics	RCV002478750	SCV002785480	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000414609	SCV003820590	uncertain significance	not provided	2020-07-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001192094	SCV003838725	uncertain significance	Cardiomyopathy	2021-10-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997692	SCV004824228	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-11-20	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 amino acid from the RYR2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/244200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.