rs79457258

chr1-237550629-G-Achr1-237550629-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP3 BP6 BS2

The NM_001035.3(RYR2):c.3152G>A(p.Arg1051His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,587,250 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1051C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:2
• Conservation: PhyloP100: 7.87

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764
• BP6: Variant 1-237550629-G-A is Benign according to our data. Variant chr1-237550629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43765.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2}.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3152G>A	p.Arg1051His	missense_variant	27/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3152G>A	p.Arg1051His	missense_variant	27/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.3152G>A	p.Arg1051His	missense_variant	27/106
RYR2	ENST00000659194.3	c.3152G>A	p.Arg1051His	missense_variant	27/105
RYR2	ENST00000609119.2	c.3152G>A	p.Arg1051His	missense_variant, NMD_transcript_variant	27/104	5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

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: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000839 AC: 17 AN: 202534 Hom.: 0 AF XY: 0.000101 AC XY: 11 AN XY: 108378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000351

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: 0.000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 331 AN: 1435032 Hom.: 0 Cov.: 30 AF XY: 0.000232 AC XY: 165 AN XY: 711068

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.0000251

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: 0.000296

Gnomad4 OTH exome AF: 0.0000672

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74428

Gnomad4 AFR AF: 0.0000963

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: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.0000665 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2023	Reported in association with DCM; however, at least one of these patients also harbored other cardiogenetic variants (Pugh et al., 2014; Walsh et al., 2017); Not 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); 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: 24503780, 27532257, 28404607) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1051 of the RYR2 protein (p.Arg1051His). This variant is present in population databases (rs79457258, gnomAD 0.02%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 24503780, 29453246). ClinVar contains an entry for this variant (Variation ID: 43765). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 31, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2023	Variant summary: RYR2 c.3152G>A (p.Arg1051His) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) and Ryanodine receptor domain (IPR003032) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 (e.g., 17 heterozygotes) in 202534 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database (v2.1, Exomes dataset). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3152G>A has been reported in the literature in individuals affected with dilated cardiomyopathy and at least one individual with suspected Catecholaminergic Polymorphic Ventricular Tachycardia (e.g., Pugh_2014, Walsh_2017, Kapplinger_2018), however without strong evidence for causality (e.g, lack of co-occurrence and co-segregation data) in all cases. These reports therefore do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29453246, 24503780, 27532257). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: 5 submitters classified the variant as VUS and 1 submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This missense variant replaces arginine with histidine at codon 1051 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 been reported in individual(s) affected with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant has also been identified in 21/233926 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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 09, 2023

This missense variant replaces arginine with histidine at codon 1051 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 RYR2-related disorders in the literature. This variant has been identified in 21/233926 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The c.3152G>A (p.R1051H) alteration is located in exon 27 (coding exon 27) of the RYR2 gene. This alteration results from a G to A substitution at nucleotide position 3152, causing the arginine (R) at amino acid position 1051 to be replaced by a histidine (H). 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.0026	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.53	T;.
Polyphen		1.0	D;.
Vest4		0.76
MVP		0.92
MPC		1.3
ClinPred		0.84	D
GERP RS		5.1
Varity_R		0.19
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: rs79457258; hg19: chr1-237713929;