rs727504976

Positions:

• chr1-237639162-G-A
• chr1-237639162-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001035.3(RYR2):​c.7076G>A​(p.Arg2359Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2359R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.53

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 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.
• BS2: High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.7076G>A	p.Arg2359Gln	missense_variant	46/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.7076G>A	p.Arg2359Gln	missense_variant	46/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.7076G>A	p.Arg2359Gln	missense_variant	46/106
RYR2	ENST00000659194.3	c.7076G>A	p.Arg2359Gln	missense_variant	46/105
RYR2	ENST00000609119.2	c.7076G>A	p.Arg2359Gln	missense_variant, NMD_transcript_variant	46/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000362 AC: 9 AN: 248804 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000390

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000961 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2014

The Arg2359Gln variant in RYR2 has been reported in 1 Japanese individual with c linical features of CPVT, who also carried a second variant of uncertain signifi cance in RYR2 (Phe4851Cys; Aizawa 2007). The Arg2359Gln variant was absent from large population studies. Computational prediction tools suggest that this varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. Additional information is needed to fully assess the cli nical significance of the Arg2359Gln variant. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 06, 2023

This variant replaces arginine with glutamine at codon 2359 of 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 16843546). This variant was also reported in one individual affected with long QT syndrome and another individual who was affected with hypertrophic cardiomyopathy (PMID: 33658040, 29434162). This variant has been identified in 9/248804 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

Oct 01, 2023

This variant replaces arginine with glutamine at codon 2359 of 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 16843546). This variant was also reported in one individual affected with long QT syndrome and another individual who was affected with hypertrophic cardiomyopathy (PMID: 33658040, 29434162). This variant has been identified in 9/248804 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2359 of the RYR2 protein (p.Arg2359Gln). This variant is present in population databases (rs727504976, gnomAD 0.03%). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia, long QT syndrome and/or hypertrophic cardiomyopathy, atrioventricular nodal reentry tachycardia (PMID: 16843546, 29434162, 32508047, 33658040). ClinVar contains an entry for this variant (Variation ID: 179595). 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

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	0.085
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N;.
REVEL	Pathogenic	0.72
Sift	Benign	0.38	T;.
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.74		Loss of glycosylation at S2358 (P = 0.1167);.;
MVP		0.94
MPC		0.78
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.62

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: rs727504976; hg19: chr1-237802462; COSMIC: COSV63670123;