rs564806219

Positions:

• chr1-237614422-C-G
• chr1-237614422-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001035.3(RYR2):​c.5294C>G​(p.Ser1765Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. S1765F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 4.86

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 Benign. Variant got -10 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.081291854).
• BP6: Variant 1-237614422-C-G is Benign according to our data. Variant chr1-237614422-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404210.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000184 (28/152306) while in subpopulation AMR AF= 0.000981 (15/15292). AF 95% confidence interval is 0.000604. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.5294C>G	p.Ser1765Cys	missense_variant	37/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.5294C>G	p.Ser1765Cys	missense_variant	37/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.5294C>G		non_coding_transcript_exon_variant	37/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.5294C>G	p.Ser1765Cys	missense_variant	37/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.5294C>G	p.Ser1765Cys	missense_variant	37/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000181 AC: 45 AN: 248986 Hom.: 0 AF XY: 0.000215 AC XY: 29 AN XY: 135060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74486

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 29, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 08, 2017	The p.Ser1765Cys variant (rs564806219) has been observed in an individual included in a cohort of hypertrophic cardiomyopathy patients (Lopes 2015), an individual with a suspected diagnosis of catecholaminergic polymorphic ventricular tachycardia who did not meet full diagnostic criteria (Jimenez-Jaimez 2015), and in a case of sudden unexplained death (Brion 2014). However, so co-segregation data is available for this variant, and it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.017% (identified in 48 out of 276,878 chromosomes). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 404210). The serine at codon 1765 is highly conserved considering 10 species up to chicken (Alamut software v2.9), although computational analyses return mixed results regarding the effect of this variant on RYR2 protein structure/function (SIFT: damaging, PolyPhen2: benign, and Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Ser1765Cys variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2024	Reported in association with HCM, ARVC, and sudden unexplained cardiac arrest/death (PMID: 24981977, 25351510, 26189708, 35819174, 32152366, 28771489); at least one patient harbored an additional cardiogenetic variant; Not 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: 26189708, 25351510, 26899768, 28404607, 37510372, 24981977, 19926015, 35819174, 32152366, 28771489) -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Jun 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Feb 02, 2017	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 28, 2021	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 26, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The p.S1765C variant (also known as c.5294C>G), located in coding exon 37 of the RYR2 gene, results from a C to G substitution at nucleotide position 5294. The serine at codon 1765 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was reported in a case of sudden cardiac death (Brion M et al. Electrophoresis, 2014 Nov;35:3111-6), and in an individual with unexplained cardiac arrest who did not meet the diagnostic criteria of catecholaminergic polymorphic ventricular tachycardia (Jiménez-Jáimez J et al. Am. J. Cardiol., 2015 Sep;116:894-9). In addition, this alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 26, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

RYR2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2023

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	0.077
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;T
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.31
Sift	Benign	0.043	D;.
Polyphen		0.019	B;.
Vest4		0.69
MutPred		0.30		Loss of disorder (P = 0.0034);.;
MVP		0.57
MPC		0.35
ClinPred		0.055	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs564806219; hg19: chr1-237777722;