rs764698152

Variant names:

• chr1-237445470-C-T
• rs764698152
• NM_001035.3:c.1240C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PM1 PP2 PP3_Strong PP5 BS2

The NM_001035.3(RYR2):​c.1240C>T​(p.Arg414Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R414H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5
• Conservation: PhyloP100: 6.07
• Publications: 16 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001035.3
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 1-237445470-C-T is Pathogenic according to our data. Variant chr1-237445470-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201212.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.1240C>T	p.Arg414Cys	missense	Exon 14 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.1240C>T	p.Arg414Cys	missense	Exon 14 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.1240C>T	p.Arg414Cys	missense	Exon 14 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.1240C>T		non_coding_transcript_exon	Exon 14 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461440 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111690

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000140 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 15, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the RYR2 gene.The R414C variant was previously published in a 16-year-old female who died while swimming competitively, and it was absent from 400 controls (Creighton et al., 2006). The R414C variant was subsequently reported in a 10-year-old boy who was experiencing ventricular fibrillation during a swimming race (Moray et al., 2011). The R414C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R414C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The R414C variant is 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). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to arginine are tolerated across species. While another variant at this same residue (R414L) and variants in nearby residues (S406L, R407S, S413T, T415R, I419F) have been reported in HGMD in association with CPVT (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Finally, the R414C variant is classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000230388.1; Landrum et al., 2016).

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 414 of the RYR2 protein (p.Arg414Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant RYR2-related conditions (PMID: 15887426, 21478052; internal data). ClinVar contains an entry for this variant (Variation ID: 201212). 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 expected to disrupt RYR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect RYR2 function (PMID: 23152493). This variant disrupts the p.Arg414 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 15466642, 16188589), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Apr 29, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.1240C>T (p.Arg414Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249004 control chromosomes (gnomAD). c.1240C>T has been observed in individuals affected with clinical features of RYR2-related disorders (Tester_2005, Creighton_J2006, Moray_2011, Medeiros-Domingo_2009, Internal data). These data indicate that the variant is likely to be associated with disease. Two publications reported this variant had no damaging effect of this variant (Loaiza_2013, Zhong_2021). The following publications have been ascertained in the context of this evaluation (PMID: 16436635, 24025405, 32899693, 19926015, 32152366, 15887426, 33825858, 21478052). ClinVar contains an entry for this variant (Variation ID: 201212). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Cardiovascular phenotype Pathogenic:1

Aug 30, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1240C>T (p.R414C) alteration is located in exon 14 (coding exon 14) of the RYR2 gene. This alteration results from a C to T substitution at nucleotide position 1240, causing the arginine (R) at amino acid position 414 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with sudden cardiac arrest after under exertion or emotion (Tester, 2005; Moray, 2011; Violano, 2022; Ambry internal data). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, this alteration disrupts a hydrogen bond interaction within the N-terminal of the protein (Borko, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 414 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental study has shown that this variant does not affect the calcium sensitivity of RYR2 channels (PMID: 23152493). This variant has been reported in two unrelated individuals affected with sudden cardiac death (PMID: 15887426, 21478052). This variant has also been reported in a healthy parent of one of the two probands, who had no history of cardiac arrhythmias (PMID: 21478052). This variant has not been identified 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.

Cardiomyopathy Uncertain:1

Feb 11, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 414 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has shown that this variant does not affect the calcium sensitivity of RYR2 channels (PMID: 23152493). This variant has been reported in two unrelated individuals affected with sudden cardiac death (PMID: 15887426, 21478052). This variant has also been reported in a healthy parent of one of the two probands, who had no history of cardiac arrhythmias (PMID: 21478052). This variant has not been identified 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.82		Loss of MoRF binding (P = 0.0076)
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.58
gMVP		0.66
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs764698152; hg19: chr1-237608770; COSMIC: COSV63693384;