rs200525962

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001035.3(RYR2):c.3380A>G(p.Glu1127Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000752 in 1,613,894 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 14 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:13

Conservation

PhyloP100: 7.29

Variant links:

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.

BP4

Computational evidence support a benign effect (MetaRNN=0.012512267).

BP6

Variant 1-237566732-A-G is Benign according to our data. Variant chr1-237566732-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=4, Uncertain_significance=4}. Variant chr1-237566732-A-G is described in Lovd as [Benign]. Variant chr1-237566732-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000598 (91/152216) while in subpopulation SAS AF= 0.00457 (22/4818). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.3380A>G	p.Glu1127Gly	missense_variant	Exon 28 of 105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.3380A>G	p.Glu1127Gly	missense_variant	Exon 28 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 link	n.3380A>G		non_coding_transcript_exon_variant	Exon 28 of 104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 link	c.3380A>G	p.Glu1127Gly	missense_variant	Exon 28 of 106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 link	c.3380A>G	p.Glu1127Gly	missense_variant	Exon 28 of 105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00108

AC:

269

AN:

249214

Hom.:

AF XY:

0.00143

AC XY:

193

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000735

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000768

AC:

1122

AN:

1461678

Hom.:

Cov.:

AF XY:

0.000960

AC XY:

698

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00548

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000514

Gnomad4 OTH exome

AF:

0.000696

GnomAD4 genome

AF:

0.000598

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00457

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000685

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000832

AC:

ExAC

AF:

0.00112

AC:

136

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Sep 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 23861362, 25650408, 26656175, 27930701, 28404607, 29350269, 33825858) -

May 30, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: : The RYR2 c.3380A>G (p.Glu1127Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 136/120770 control chromosomes (including 4 homozygotes) from ExAC at a frequency of 0.0011261, which is approximately 20 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. It is more common in South Asian subpopulation with an allele frequency of 0.0055 (92/16512 chromosomes). This variant has been found in two patients (one with HCM and another with Brugada syndrome) without strong evidence for causality (Bottillo_2015, Le Scouarnec_2015). The HCM patient with this variant also carried another VUS MYBPC3 p.M555T. In ClinVar while three clinical laboratories have classified this variant as likely benign/benign, other three have classified it as VUS; all without evidence for independent evaluation. This variant is also located outside of mutational "hotspots" region (exons 1-16) (Medeiros-Domingo, A et al., 2009; PMID: 19926015). Taken together, this variant is classified as likely benign. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 20, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

UPDATE on 3/20/2017: gnomAD shows this variant to have an allele frequency of 0.55% in South Asians, including 5 homozygotes, and to be present in 275 individuals out of the 140,000 in gnomAD total. -

May 27, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR2: BS1, BS2 -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. 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) (PMID: 12459180, PMID: 27646203, PMID: 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM and PMID: 22787013). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of catecholaminergic polymorphic ventricular tachycardia, 1 (MIM#604772). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SPRY domain 2 (NCBI, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported as a VUS, but more recently as likely benign or benign (LOVD, ClinVar, Cardiodb). It has also been observed in several individuals with sudden unexplained death, hypertrophic cardiomyopathy or catecholaminergic polymorphic ventricular tachycardia (PMID: 28404607, PMID: 29350269, PMID: 27054166). (I) 1206 - This variant has been shown to be paternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiomyopathy

Uncertain:1Benign:1

Jun 21, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sudden cardiac death

Uncertain:1

May 14, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2

Uncertain:1

Feb 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sudden unexplained death

Benign:1

Nov 28, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

The RYR2 Glu1127Gly has been identified previously in individuals with a broad range of cardiac conditions. The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.001 which is higher then expected for inherited cardiac disease. In summary, based on the high allele frequency in the general population we classify RYR2 Glu1127Gly as "benign". -

not specified

Benign:1

Apr 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu1127Gly in exon 28 of RYR2: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (92/16512) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs200525962). -

Cardiovascular phenotype

Benign:1

Dec 15, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.3

L;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.3

D;.

REVEL

Uncertain

0.50

Sift

Uncertain

0.014

D;.

Polyphen

0.98

D;.

Vest4

0.91

MVP

0.55

MPC

1.3

ClinPred

0.12

GERP RS

5.3

Varity_R

0.42

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over