rs794728721

chr1-237445489-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001035.3(RYR2):c.1259G>A(p.Arg420Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,386 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. R420W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 6.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr1-237445488-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201214.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=9}.
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 1-237445489-G-A is Pathogenic according to our data. 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. Variant chr1-237445489-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.1259G>A	p.Arg420Gln	missense_variant	14/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.1259G>A	p.Arg420Gln	missense_variant	14/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.1259G>A	p.Arg420Gln	missense_variant	14/106
RYR2	ENST00000659194.3	c.1259G>A	p.Arg420Gln	missense_variant	14/105
RYR2	ENST00000609119.2	c.1259G>A	p.Arg420Gln	missense_variant, NMD_transcript_variant	14/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461386 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726978

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 19, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg420Gln (R420Q; c.1259 G>A) in the RYR2 gene This variant has been previously reported in at least 5 unrelated individuals with CPVT. There is no published segregation data. Medeiros-Domingo et al. (2009) reported Arg420Gln in two unrelated individuals from a group diagnosed with either CPVT or gene-negative exercise-induced LQTS (QTc < 480 msec). van der Werf et al. (2011) observed it in one individual with CPVT. GeneDx reports finding it in two other unrelated individuals tested for CPVT. Variation at this amino acid and at other nearby residues has been associated with CPVT, suggesting the functional importance of this codon and this protein region: Arg420Trp, Thr415Arg, Ile419Phe (HGMD via GeneDx). Amino acid 420 falls in the N-terminal domain of RYR2, where other disease-causing mutations have been shown to cluster. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged arginine with a polar glutamine. The arginine at this location is highly conserved across 42/43 mammalian species sequenced. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.994. In total the variant has not been seen in ~7200 individuals from published controls and publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however. (Our patient has Mexican and Spanish ancestry.) There is no variation at this codon in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals (as of May 28, 2013). No non-clinical variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). No variation at this codon is present in 1000 Genomes, which contains 66 individuals of Mexican ancestry from Los Angeles, as of January 8, 2013. (Out of 1092 genotypes in phase 1, there are 66 people of Mexican ancestry from LA, 55 Puerto Ricans, 60 Colombians from Medellin, totaling 181 Hispanic or Latino individuals.) The variant was not observed in published controls: Medeiros-Domingo et al. (2009) did not find the variant in 200 controls (100 Caucasian and 100 Black). van der Werf et al. (2011) and GeneDx did not report additional controls. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2023	Reported in association with CPVT and/or sudden unexplained death in the published literature (Medeiros-Domingo et al., 2009; van der Werf et al., 2011; Ohno et al., 2015; Shigemizu et al. 2015); Published functional studies demonstrate a damaging effect (altered the orientations of RYR2 channel domain which is required for protein stability) (Kimlicka et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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); This variant is associated with the following publications: (PMID: 24025405, 25372681, 26114861, 21616285, 22334434, 25440180, 26153920, 26132555, 27452199, 27761165, 27916777, 28422759, 28449774, 28012210, 29434162, 31112425, 31337358, 31535183, 32605058, 34135346, 34076677, 19926015, 23871484) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 13, 2016	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the RYR2 protein (p.Arg420Gln). 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 catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 19926015, 23595086, 25440180, 26132555, 28449774). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201215). 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 80%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 26153920, 28422759). 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: 21616285, 22221940, 22373669, 22787013). 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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

The p.R420Q pathogenic mutation (also known as c.1259G>A), located in coding exon 14 of the RYR2 gene, results from a G to A substitution at nucleotide position 1259. The arginine at codon 420 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been seen in several cohorts of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), suspected long QT syndrome, or sudden death (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009; 54(22):2065-74; van der Werf C et al. J Am Coll Cardiol. 2011; 57(22):2244-54; Lahrouchi N et al. J Am Coll Cardiol. 2017;69(17):2134-2145). This alteration also segregated with disease in a large family with CPVT (Domingo D et al. Rev Esp Cardiol (Engl Ed). 2015; 68(5):398-407). In addition, functional in vitro studies suggest this alteration causes conformational changes that likely activate the channel (Kimlicka L et al. Structure. 2013; 21(8):1440-9), while additional assays, utilizing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) or knock-in (KI) mouse models, showed that this alteration disrupts protein function, resulting in increased diastolic Ca2+ release (Novak A et al. J Cell Mol Med. 2015;19:2006-18; Wang YY et al. JCI Insight. 2017;2(8). Epub ahead of print. doi:10.1172/jci.insight.91872). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Long QT syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

Medical Research Institute, Tokyo Medical and Dental University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.012	D;.
Polyphen		0.99	D;.
Vest4		0.93
MutPred		0.84		Loss of MoRF binding (P = 0.0336);.;
MVP		0.97
MPC		0.76
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.73

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

Other links and lift over

dbSNP: rs794728721; hg19: chr1-237608789; COSMIC: COSV63679796;