rs533330664

chr1-237550628-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.3151C>T(p.Arg1051Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000641 in 1,590,734 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R1051H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (2 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 0.781

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 Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.23706189).
• BP6: Variant 1-237550628-C-T is Benign according to our data. Variant chr1-237550628-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201235.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000674 (97/1438582) while in subpopulation SAS AF= 0.000688 (57/82804). AF 95% confidence interval is 0.000545. There are 2 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3151C>T	p.Arg1051Cys	missense_variant	27/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3151C>T	p.Arg1051Cys	missense_variant	27/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.3151C>T	p.Arg1051Cys	missense_variant	27/106
RYR2	ENST00000659194.3	c.3151C>T	p.Arg1051Cys	missense_variant	27/105
RYR2	ENST00000609119.2	c.3151C>T	p.Arg1051Cys	missense_variant, NMD_transcript_variant	27/104	5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000910 AC: 19 AN: 208890 Hom.: 0 AF XY: 0.000116 AC XY: 13 AN XY: 112040

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000609

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000674 AC: 97 AN: 1438582 Hom.: 2 Cov.: 30 AF XY: 0.0000968 AC XY: 69 AN XY: 713134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000688

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000282

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000997 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	Has been identified independently and in association with other cardiac variants in patients with cardiomyopathy or arrhythmia (Lopez et al., 2013; Lee et al., 2015; Landstrom et al., 2017); Reported in ClinVar (ClinVar Variant ID# 201235; Landrum et al., 2016); 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: 25925909, 28404607, 23396983) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 16, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely pathogenic by GeneDx. It has a Max MAF of 0.07% in ExAC (7 alleles) and 0.06% in gnomAD (16 alleles). The AA at this position is conserved. In HGMD there is another variant at this position: Arg1051Pro. In GI there are 2 other variants at this position: Arg1051Arg (likely benign) and Arg1051His (VUS4). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2019	Variant summary: RYR2 c.3151C>T (p.Arg1051Cys) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain & B30.2/SPRY domain 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 9.7e-05 in 205652 control chromosomes, predominantly at a frequency of 0.00064 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 25.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3151C>T has been reported in the literature in affected individuals (Hauser_2018, Landstrom_2017, Lopes_2013). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variants have been reported in our internal database (MYH7 c.2681A>G, p.Glu894Gly) and also, published (TNNI3 c.485G>A, p.R162Q) (Lopes_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 04, 2023

This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 19/208890 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. -

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

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Apr 25, 2022

The c.3151C>T variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS) and Indian Exome Database. The heterozygous state of the variant is present in Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD), at a low frequency. The variant is not present in our in-house exome database. The variant was previously reported in the literatures in similarly affected individuals (PMID: 23396983, 28404607, 29368431). The variant was reported to Clinvar (Accession: VCV000201235.11) with conflicting interpretations of pathogenicity (Uncertain significance/likely benign). In-silico pathogenicity prediction programs like PolyPhen-2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. Alternative variants in the same amino acid position (Arg1051His, Arg1051Pro) were previously reported in the literatures in similarly affected individuals (PMID: 27532257, 19216760) and reported to Human Genome Mutation database (HGMD IDs: CM1616928, CM090703) -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 20, 2023

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.83	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.68
Sift	Benign	0.35	T;.
Polyphen		1.0	D;.
Vest4		0.86
MVP		0.87
MPC		0.57
ClinPred		0.43	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.78

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: rs533330664; hg19: chr1-237713928; COSMIC: COSV63683432; COSMIC: COSV63683432;