rs200236750

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001035.3(RYR2):c.3320C>T(p.Thr1107Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1107T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 1 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:10

Conservation

PhyloP100: 1.90

Publications

31 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 2
Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 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, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.09495711).

BP6

Variant 1-237566672-C-T is Benign according to our data. Variant chr1-237566672-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43768.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000526 (80/152118) while in subpopulation NFE AF = 0.00097 (66/68024). AF 95% confidence interval is 0.000782. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.3320C>T	p.Thr1107Met	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.3320C>T	p.Thr1107Met	missense_variant	Exon 28 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.3320C>T	p.Thr1107Met	missense_variant	Exon 28 of 106			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.3320C>T		non_coding_transcript_exon_variant	Exon 28 of 104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000421

AC:

105

AN:

249172

AF XY:

0.000436

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000593

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000815

AC:

1192

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

562

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.000893

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000925

AC:

1029

AN:

1111852

Other (OTH)

AF:

0.00131

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000526

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000548

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000600

AC:

ExAC

AF:

0.000322

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Feb 02, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

- -

Dec 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23861362, 27538377, 27435932, 22374134, 19926015, 24025405, 20157052, 22677073, 26573135, 25370123, 28404607, 28567303, 30403697, 29396286) -

Apr 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR2: BP4 -

Sep 07, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Jan 25, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Thr1107Met variant in RYR2 has been reported in an individual with CVPT, a case of SIDS, a Japanese family with HCM, an individual with DCM, and as a secondary finding in an individual with oculocutaneous albinism without mention of cardiac phenotype (Medeiros-Domingo et al 2009, Methner et al. 2016, Stavropolous et al. 2017, Noboru et al. 2006 (abstract only), LMM data). It has been reported in ClinVar (Variation ID #43768). In vitro functional studies provide some evidence that the p.Thr1107Met variant may impact protein function (Tang et al. 2012). However, these types of assays may not accurately represent biological function. This variant has been identified in 79/126600 of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200236750). Threonine (Thr) at position 1107 is not conserved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, due to conflicting data, the clinical significance of the p.Thr1107Met variant is uncertain. -

Dec 07, 2021

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: RYR2 c.3320C>T (p.Thr1107Met) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 & B30.2/SPRY domain 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 0.00042 in 249172 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3320C>T has been reported in the literature in individuals affected with Arrhythmia and other cardiopathologies (example: Fujino_2006, Tester_2012, Medeiros-Domingo_2009, Ghazani_2017, Landstrom_2017, Methner_2016, Rangaraju_2018, Roston_2018, Stavropoulos_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.2398+5G>T; CASQ2 IVS5+1G>C (c.606+1G>C); MYH7 c.1447G>A/p.E483K) (Roston_2018, Tester_2012, Internal database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example: Tang_2012). The most pronounced variant effect results in >50%-90% of normal activity. Seven ClinVar submitters have assessed this variant since 2014: three report the variant as likely benign, three as of uncertain significance, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype

Uncertain:1Benign:1

Jun 10, 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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Death in infancy

Pathogenic:1

Mar 27, 2015

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Nov 05, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RYR2-related disorder

Benign:1

Sep 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.095

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.11

N;.

PhyloP100

1.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0080

D;T

Polyphen

0.58

P;.

Vest4

0.78

MVP

0.70

MPC

0.50

ClinPred

0.016

GERP RS

5.4

Varity_R

0.094

gMVP

0.59

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over