Submissions for variant NM_001035.3(RYR2):c.3721G>A (p.Val1241Ile)

gnomAD frequency: 0.00008  dbSNP: rs185715460

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036736	SCV000060391	likely benign	not specified	2018-11-05	criteria provided, single submitter	clinical testing	The p.Val1241Ile variant in RYR2 is classified as likely benign because it has b een identified in 0.03% (33/128294) of European chromosomes by gnomAD (http://gn omad.broadinstitute.org). Valine (Val) at position 1241 is highly conserved in m ammals and most evolutionarily distant species, though frog and yellowbelly puff erfish carry an isoleucine (Ile; this variant). Additional computational predict ion tools suggest that this variant may not impact the protein. ACMG/AMP Criteri a applied: BS1_Supporting, BP4.
Eurofins Ntd Llc (ga)	RCV000724637	SCV000229305	uncertain significance	not provided	2015-03-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000724637	SCV000616959	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a cohort of individuals undergoing clinical whole exome sequencing in published literature (Landstrom et al., 2017), although further details regarding the number of individuals found to harbor this variant, the indication for testing, and any follow-up cardiac evaluations were not described; Also reported in a patient with atrioventricular nodal reentry tachycardia (Luo et al., 2020); however, specific clinical information was not provided; In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 28404607, 32508047)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001824587	SCV000760662	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1241 of the RYR2 protein (p.Val1241Ile). This variant is present in population databases (rs185715460, gnomAD 0.03%). 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: 43775). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768761	SCV000900131	uncertain significance	Cardiomyopathy	2016-03-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768761	SCV000914068	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1241 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypokalemic periodic paralysis and cardiac arrhythmia (PMID: 36310724), in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930), and in a healthy control as well (PMID: 32508047). This variant occurs at an appreciable frequency in the general population and has been identified in 45/280440 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036736	SCV001338096	likely benign	not specified	2024-11-01	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.3721G>A (p.Val1241Ile) results in a conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 249044 control chromosomes, predominantly at a frequency of 0.00027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05). c.3721G>A has been reported in the literature in individuals affected with catecholaminergic polymorphic ventricular tachycardia (Landstrom_2017_Sagray_2022, Hata_2022, Olubando_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36070930, 28404607, 32152366, 36310724). ClinVar contains an entry for this variant (Variation ID: 43775). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV003996277	SCV004817076	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1241 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypokalemic periodic paralysis and cardiac arrhythmia (PMID: 36310724), in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930), and in a healthy control as well (PMID: 32508047). This variant occurs at an appreciable frequency in the general population and has been identified in 45/280440 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.
Ambry Genetics	RCV004018809	SCV004945115	uncertain significance	Cardiovascular phenotype	2022-07-15	criteria provided, single submitter	clinical testing	The c.3721G>A (p.V1241I) alteration is located in exon 30 (coding exon 30) of the RYR2 gene. This alteration results from a G to A substitution at nucleotide position 3721, causing the valine (V) at amino acid position 1241 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV001824587	SCV002075190	not provided	Catecholaminergic polymorphic ventricular tachycardia 1		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-18-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.