1-237445488-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001035.3(RYR2):c.1258C>T(p.Arg420Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,638 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R420Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 4.16

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 Pathogenic. Variant got 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001035.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-237445489-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 1-237445488-C-T is Pathogenic according to our data. Variant chr1-237445488-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 201214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237445488-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.1258C>T	p.Arg420Trp	missense_variant	Exon 14 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.1258C>T	p.Arg420Trp	missense_variant	Exon 14 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 link	n.1258C>T		non_coding_transcript_exon_variant	Exon 14 of 104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 link	c.1258C>T	p.Arg420Trp	missense_variant	Exon 14 of 106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 link	c.1258C>T	p.Arg420Trp	missense_variant	Exon 14 of 105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249018

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135092

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia

Pathogenic:3

May 07, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1258C>T (p.Arg420Trp) variant in RYR2 gene, encoding ryanodine receptor 2, has been identified in numerous individuals (>10) with catecholaminergic polymorphic ventricular tachycardia (CPVT) and/or sudden unexpected death (PMID: 12106942, 15544015, 17062961, 19926015, 21616285). This variant has been reported to co-segregate with disease in one family with incomplete penetrance (PMID: 12106942). This variant has also been reported in two families with mild disease expression in variant carriers (PMID: 22787013, 22373669). This variant was also observed in three affected individuals in one family (PMID: 26743238). In-vitro functional studies revealed that this variant results in higher levels of fractional calcium release by RYR2 channels (PMID: 22374134). In-vivo functional studies using knock-in mouse models revealed that the mutant mice showed significant increases in thymus and spleen weights and have a significantly higher occurrence of arrhythmias in response to heart stimulants compared to wild-type mice (PMID: 25087098, 25193700). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score 0.88). This variant has been classified as pathogenic by multiple submitters in ClinVar (ID: 201214). Another missense variant affecting the same amino acid residue, p.Arg420Gln, has also been classified as pathogenic or likely pathogenic by multiple submitters in ClinVar (ID: 201215). This variant is rare (3/249018 chromosomes; 0.0012%) in the general population database (gnomAD). Therefore, the c.1258C>T (p.Arg420Trp) variant in RYR2 gene is classified as pathogenic. -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in RYR2 is predicted to replace arginine with tryptophan at codon 420, p.(Arg420Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a cytoplasmic helical region in the N-terminal domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (1/17,960 alleles) in the East Asian population, which is consistent with RYR2-related disease. The variant has been identified in multiple individuals with sudden unexplained cardiac death or a clinical diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT), and segregates with disease in multiple families (PMID: 12106942, 15544015, 17062961, 21616285, 22373669, 26743238). A knock-in mouse model for the variant exhibits arrhythmogenesis with abnormal calcium dynamics in cardiomyocytes (PMID: 25193700). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.88). Another missense variant c.1259G>A, p.(Arg420Gln) in the same codon with a smaller physicochemical difference has been classified as pathogenic for CPVT (ClinVar ID: 201215). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Moderate, PM5, PS4_Supporting, PM2_Supporting, PP3. -

Jun 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg420Trp in RYR2 has been identified in 6 individuals (1 child, 2 adolesc ents, 3 adults) with a clinical diagnosis of CPVT or sudden unexplained death (B auce 2002, Tester 2004, Nishio 2006, van der Werf 2012) and segregated with dise ase in at least 6 affected relatives from two families (Bauce 2002, van der Werf 2011). The p.Arg420Trp variant has been identified in 1/8604 East Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs190140598). Please note that for diseases with clinical variability or r educed penetrance, pathogenic variants may be present at a low frequency in the general population. A pathogenic role is also supported by studies of mice carry ing the variant (Okudaira 2014). In summary, this variant meets our criteria to be classified as pathogenic for CPVT in an autosomal dominant manner (http://www .partners.org/personalizedmedicine/LMM) based upon segregation studies and funct ional evidence. -

Catecholaminergic polymorphic ventricular tachycardia 1

Pathogenic:2

Jan 18, 2024

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 tryptophan, which is neutral and slightly polar, at codon 420 of the RYR2 protein (p.Arg420Trp). This variant is present in population databases (rs190140598, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 21616285, 22221940, 22373669, 22787013). ClinVar contains an entry for this variant (Variation ID: 201214). 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 expected to disrupt RYR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 22374134, 25193700). This variant disrupts the p.Arg420 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25440180, 26153920, 28422759, 28449774). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

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 Pathogenic. 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. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in one of the well established missense variant hotspots found in this protein (Decipher, PMID: 19926015, PMID: 25193700). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.Arg420Gln) has been reported multiple times as pathogenic, and has been observed in individuals with catecholaminergic polymorphic with ventricular tachycardia (CPVT) (ClinVar, PMID: 19926015). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described multiple times as pathogenic, and has been observed in many families with CPVT, commonly with incomplete penetrance (ClinVar, VCGS, PMID: 28158428). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Knock-in mice have been demonstrated to have impaired depolarization-induced calcium oscillation in cardiomyocytes, prolonged decay time and abnormal calcium ion release (PMID: 25193700). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiomyopathy

Pathogenic:1Uncertain:1

Nov 19, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.1258C>T (p.Arg420Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249018 control chromosomes (gnomAD). c.1258C>T has been reported in the literature in multiple individuals and families affected with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) or Sudden Cardiac Death (e.g. Bauce_2002, Tester_2004, Adler_2016, van der Werf_2012, Nannenberg_2012), and was shown to segregate with the disease in several families, although with a reduced penetrance (Bauce_2002, van der Werf_2012, Nannenberg_2012). These data indicate that the variant is very likely to be associated with disease. This variant was also found in one patient in cardiomyopathy panel testing in our laboratory. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in higher levels of fractional calcium release by RYR2 channels (Tang_2012). In addition, a knock-in mouse model of the R420W variant showed susceptibility to arrhythmias in response to heart stimulants (Okudaira_2014). Another missense variant affecting the same amino acid (R420Q) has been also reported in patients (HGMD), indicating the functional importance of this residue. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 20, 2021

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

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2

Pathogenic:1

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ventricular fibrillation

Pathogenic:1

Dec 15, 2015

Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:1

Dec 14, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with CPVT and/or sudden unexplained death in patients referred to GeneDx and in the published literature (Bauce et al., 2002; Nishio et al., 2006; Medeiros-Domingo et al., 2009; Anderson et al., 2016; Kawata et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Published functional studies in HEK293 cells and mouse models demonstrate a damaging effect on RYR2 receptor function (Tang et al., 2012; Okudaira et al., 2014); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 201214; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25372681, 24025405, 22221940, 15544015, 23871484, 21616285, 31231889, 22373669, 25193700, 17062961, 12934820, 26332594, 22383456, 19926015, 12106942, 22787013, 26082524, 27114410, 27452199, 27538377, 28713282, 25087098, 26153920, 28422759, 28449774, 30170228, 29925740, 29434162, 29759671, 31112425, 30898243, 30909845, 31402444, 22374134, 30847666, 26582918) -

Cardiovascular phenotype

Pathogenic:1

Dec 01, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R420W pathogenic mutation (also known as c.1258C>T), located in coding exon 14 of the RYR2 gene, results from a C to T substitution at nucleotide position 1258. The arginine at codon 420 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in numerous individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and/or sudden unexpected death (Tester DJ et al. Mayo Clin. Proc. 2004;79:1380-4; Nishio H et al. Circ. J. 2006;70:1402-6; Medeiros-Domingo A et al. J. Am. Coll. Cardiol. 2009;54:2065-74; van der Werf C et al. Circ Arrhythm Electrophysiol. 2012;5:748-56; Kawata H et al. Circ. J., 2016 Aug;80:1907-15). This variant has also been reported to segregate with disease (Bauce B et al. J. Am. Coll. Cardiol. 2002;40:341-9; Nannenberg EA et al. Circ Cardiovasc Genet. 2012;5:183-9). Functional studies performed in mammalian cell lines suggest this alteration has an impact on calcium signaling, and mice with this variant have a significantly higher occurrence of arrhythmias in response to heart stimulants than wild-type mice (Tang Y et al. Circ. Res. 2012;110:968-77; Okudaira N et al. Biochem. Biophys. Res. Commun. 2014;452:665-8). In addition, a pathogenic mutation (p.R420Q) has been described in the same codon (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009; 54(22):2065-74). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.2

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.94

MVP

0.98

MPC

1.0

ClinPred

0.99

GERP RS

5.8

Varity_R

0.65

gMVP

0.80

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