rs201312753

Variant names:

• chr1-237566708-G-A
• rs201312753
• NM_001035.3:c.3356G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP2 PP3 BP6 BS1 BS2

The NM_001035.3(RYR2):​c.3356G>A​(p.Arg1119His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,613,802 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. R1119C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 8.15

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.81
• BP6: Variant 1-237566708-G-A is Benign according to our data. Variant chr1-237566708-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196110.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000177 (27/152126) while in subpopulation NFE AF= 0.000294 (20/68004). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.3356G>A	p.Arg1119His	missense_variant	Exon 28 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.3356G>A	p.Arg1119His	missense_variant	Exon 28 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.3356G>A		non_coding_transcript_exon_variant	Exon 28 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.3356G>A	p.Arg1119His	missense_variant	Exon 28 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.3356G>A	p.Arg1119His	missense_variant	Exon 28 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 249230 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 135210

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000341 AC: 499 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.000314 AC XY: 228 AN XY: 727122

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74320

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000243 AC: 1

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jun 08, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

We consider the c.3356G>A (p.Arg1119His) variant to be a variant of uncertain significance, probably benign. It was found in our patient along with a de novo Likely Pathogenic variant in the RYR2 gene that explains the patient’s phenotype. The p.Arg1119His variant is present in population-based cohorts but has not been reported in the literature in association with disease. The variant was reported in 41 / 277,124 (0. 015%) alleles in the gnomAD dataset (http://gnomad.broadinstitute.org), which includes variant calls from 123,136 exome sequences and 15,496 genome sequences from unrelated individuals of non-Finnish European, Finnish, African, Latino, Ashkenazi Jewish, East Asian, and South Asian descent. The highest ethnicity-specific minor allele frequency is 0.024% in non-Finnish Europeans. The gnomAD dataset is comprised of multiple cohorts, some of which were recruited from the general population and others that include individuals sequenced as part of various disease-specific and population genetic studies; the phenotypes of individuals are not publicly available. This is a conservative amino acid change from a positively-charged Arginine to a positively-charged Histidine. According to the Invitae report, in silico algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25"). The arginine at codon 1119 is highly conserved across vertebrate evolution. However, the variant does not occur within one of the three “hotspots” in the RYR2 gene, where other pathogenic variants have been reported to cluster (Medeiros-Domingo et al., 2009). Furthermore, pathogenic variants have not been reported to ClinVar in association with arrhythmia at nearby residues (+/- 10), indicating this region of the protein may tolerate change. In summary, we consider this variant to be a rare missense change with uncertain impact on protein function. In light of this evidence, we consider it to be a variant of uncertain significance, likely benign. -

Feb 09, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); Identified in individuals with cardiomyopathy referred for genetic testing at GeneDx and in the published literature, and reported in patients with sudden unexplained death (PMID: 25351510, 35276540, 37589201); This variant is associated with the following publications: (PMID: 25925909, 35276540, 19926015, 37589201, 25351510) -

Cardiomyopathy Uncertain:1 Benign:1

May 23, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Nov 01, 2022

Institute of Human Genetics, University of Goettingen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Feb 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.3356G>A (p.Arg1119His) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249230 control chromosomes. The observed variant frequency is approximately 5-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 benign. c.3356G>A has been reported in the literature in individuals affected with Sudden cardiac death and DCM, without strong evidence for causality (Neubauer_2022, Lopes_2015). These report(s) 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: 35276540, 25351510). ClinVar contains an entry for this variant (Variation ID: 196110). Based on the evidence outlined above, the variant was classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 01, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Pathogenic	0.67
Sift	Benign	0.043	D;.
Polyphen		1.0	D;.
Vest4		0.83
MVP		0.88
MPC		1.3
ClinPred		0.75	D
GERP RS		5.4
Varity_R		0.23
gMVP		0.80

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: rs201312753; hg19: chr1-237730008; COSMIC: COSV99053558;