rs201749277

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001035.3(RYR2):c.10528C>A(p.Arg3510Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000759 in 1,595,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3510H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 2.38

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 Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.28178707).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.10528C>A	p.Arg3510Ser	missense_variant	73/105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.10528C>A	p.Arg3510Ser	missense_variant	73/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.1 linkuse as main transcript	c.334C>A	p.Arg112Ser	missense_variant	4/12			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 linkuse as main transcript	n.*1563C>A		non_coding_transcript_exon_variant	71/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 linkuse as main transcript	n.*1563C>A		3_prime_UTR_variant	71/104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

248194

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

134732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000769

AC:

111

AN:

1443242

Hom.:

Cov.:

AF XY:

0.0000737

AC XY:

AN XY:

719052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000994

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000259

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2015	The p.Arg3510Ser variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/67128 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s201749277). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Arg3510Ser variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2021	Variant summary: RYR2 c.10528C>A (p.Arg3510Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 248194 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10528C>A has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia or related diseases (Landstrom_2017, Lin_2017, Luo_2020). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2022	This missense variant replaces arginine with serine at codon 3510 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with atrioventricular nodal reentry tachycardia (PMID: 29396561, 32508047) and in an individual affected with sudden unexplained death (PMID: 29247119). This variant has also been identified in 12/279572 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. -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

This missense variant replaces arginine with serine at codon 3510 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with atrioventricular nodal reentrant tachycardia (PMID: 29396561, 32508047) and in an individual affected with sudden unexplained death (PMID: 29247119). This variant has also been identified in 12/279572 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2017

A variant of uncertain significance has been identified in the RYR2 gene. The R3510S variant has been reported in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017); however, specific details regarding the indication for genetic testing or the patient's clinical phenotype were not described. This variant has been observed in two other individuals referred for cardiomyopathy genetic testing at GeneDx, although one of these individuals harbored additional cardiogenetic variants, including a pathogenic variant in a different gene, and no segregation data are available for either case observed at GeneDx. Additionally, this variant has been observed 4/66204 (0.006%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R3510S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, R3510S is 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). -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2022

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 3510 of the RYR2 protein (p.Arg3510Ser). This variant is present in population databases (rs201749277, gnomAD 0.007%). This missense change has been observed in individual(s) with arrhythmia and/or sudden unexplained death (PMID: 29247119, 32508047). ClinVar contains an entry for this variant (Variation ID: 201302). 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 not expected to disrupt RYR2 protein function. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2022

The c.10528C>A (p.R3510S) alteration is located in exon 73 (coding exon 73) of the RYR2 gene. This alteration results from a C to A substitution at nucleotide position 10528, causing the arginine (R) at amino acid position 3510 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;T

Eigen

Benign

-0.014

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.9

D;.

REVEL

Uncertain

0.51

Sift

Benign

0.11

T;.

Polyphen

0.088

B;.

Vest4

0.63

MVP

0.95

MPC

0.46

ClinPred

0.19

GERP RS

5.7

Varity_R

0.31

gMVP

0.54

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