rs202040519

Positions:

• chr1-237493065-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_001035.3(RYR2):​c.1939C>T​(p.Arg647Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,613,520 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R647H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 3.15

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 Likely_benign. Variant got -2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1939C>T	p.Arg647Cys	missense_variant	19/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1939C>T	p.Arg647Cys	missense_variant	19/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1939C>T		non_coding_transcript_exon_variant	19/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1939C>T	p.Arg647Cys	missense_variant	19/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.1939C>T	p.Arg647Cys	missense_variant	19/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 248508 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1461372 Hom.: 0 Cov.: 33 AF XY: 0.000220 AC XY: 160 AN XY: 726914

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74324

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 2 (MIM#600996) and ventricular tachycardia, catecholaminergic polymorphic, 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 (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (41 heterozygotes, 0 homozygotes). (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) 0600 - Variant is located in the annotated RIH domain (NCBI, PDB). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.Arg647His) has been reported multiple times as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS (LOVD, ClinVar, PMID: 30615648, PMID: 28404607), once as likely benign (LOVD) and once as likely pathogenic in a patient from a large arrhythmia cohort (PMID: 30847666). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 647 of the RYR2 protein (p.Arg647Cys). This variant is present in population databases (rs202040519, gnomAD 0.03%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 30847666, 32152366). ClinVar contains an entry for this variant (Variation ID: 178115). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2024	Identified in a cohort of stillbirths without chromosomal abnormalities (PMID: 30615648); 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: 19926015, 28404607, 30847666, 30122538, 32152366, 33789662, 30615648) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 02, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2013

The Arg647Cys variant in RYR2 has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 1/8366 Eu ropean American chromosomes and 1/3992 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs202040519). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. At this time, additional information is needed to fully assess the clinical significance of this variant. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 26, 2023

This missense variant replaces arginine with cysteine at codon 647 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 41/279906 chromosomes 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. -

Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 10, 2022

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 10, 2022

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The c.1939C>T (p.R647C) alteration is located in exon 19 (coding exon 19) of the RYR2 gene. This alteration results from a C to T substitution at nucleotide position 1939, causing the arginine (R) at amino acid position 647 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0090	D;.
Polyphen		1.0	D;.
Vest4		0.68
MVP		0.92
MPC		1.3
ClinPred		0.75	D
GERP RS		5.3
Varity_R		0.29
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202040519; hg19: chr1-237656365; COSMIC: COSV99053489;