rs1401116572

Positions:

• chr1-237441382-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):​c.1069G>A​(p.Gly357Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,490 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. G357D) 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:9
• Conservation: PhyloP100: 9.99

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a turn (size 2) in uniprot entity RYR2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr1-237441383-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2037310.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-237441382-G-A is Pathogenic according to our data. Variant chr1-237441382-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 519533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237441382-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1069G>A	p.Gly357Ser	missense_variant	13/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1069G>A	p.Gly357Ser	missense_variant	13/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1069G>A		non_coding_transcript_exon_variant	13/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1069G>A	p.Gly357Ser	missense_variant	13/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.1069G>A	p.Gly357Ser	missense_variant	13/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727016

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in an increase in caffeine sensitivity and store overload-induced calcium release activity compared to wild-type while under conditions that mimic catecholaminergic stress (PMID: 25814417); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24025405, 24136861, 28961276, 28789916, 30847666, 31112425, 30063211, 19926015, 35176171, 30763784, 35135837, 22068070, 25814417) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 357 of the RYR2 protein (p.Gly357Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 22068070, 25814417; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 519533). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. Experimental studies have shown that this missense change affects RYR2 function (PMID: 25814417, 28961276). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 (CPVT) (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 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 found within an established missense variant hotspot within the N-terminal domain (PMID: 19926015). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This variant (p.Gly357Asp) was classified as a VUS, and identified in an individual as an incidental finding (PMID: 28404607). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (LOVD, ClinVar), and observed in multiple families with incomplete penetrance, with either an unspecific arrhythmia, or catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, PMID: 22068070, PMID: 25814417, PMID: 30763784, PMID: 30847666). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells demonstrated a greater sensitivity to caffeine and forskolin, mimicking catecholaminergic stress conditions (PMID: 25814417). (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:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 07, 2022

This missense variant replaces glycine with serine at codon 357 in the cytoplasmic MIR domain 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). Functional studies have shown that this variant causes instability of the N-terminal region and increased propensity for spontaneous calcium release from the sarcoplasmic reticulum in conditions that mimic beta-adrenergic stimulations (PMID: 25814417, 28961276). This variant has been identified in about 180 individuals from a large, multi-generational pedigree affected with catecholaminergic polymorphic ventricular tachycardia (CPVT), including 9 individuals affected with sudden cardiac death during youth and 40 individuals who received an implantable cardioverter defibrillator (PMID: 25814417). In the serial exercise treadmill test, 74% of the carriers exhibited complex ventricular arrhythmias. This variant has also been reported in another 12 individuals affected with CPVT from at least 8 different families (PMID: 19926015, 22068070, 24136861, 29453246, 30763784, 31112425, 32091590, communication with an external laboratory, ClinVar SCV001817325.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2021

The p.G357S pathogenic mutation (also known as c.1069G>A), located in coding exon 13 of the RYR2 gene, results from a G to A substitution at nucleotide position 1069. The glycine at codon 357 is replaced by serine, an amino acid with similar properties. This mutation has been previously described in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Heiner JD et al. Pediatr Emerg Care, 2011 Nov;27:1065-8). This mutation was identified in a very large family with multiple cases of CPVT, including sudden cardiac death in youth, and strong segregation with the disease was demonstrated (Wangüemert F et al. Heart Rhythm, 2015 Jul;12:1636-43). In vitro studies suggested that this mutation resulted in reduced protein expression and increased release of calcium from intracellular stores under conditions that mimic beta-adrenergic stimulation (Wangüemert F et al. Heart Rhythm, 2015 Jul;12:1636-43; Liu Y et al. PLoS ONE, 2017 Sep;12:e0184177). 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	0.50
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Pathogenic	0.78
Sift	Benign	0.054	T;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.89		Loss of ubiquitination at K355 (P = 0.0777);.;
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.63

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: rs1401116572; hg19: chr1-237604682; COSMIC: COSV100773614;