1-237369589-G-A

Position:

• chr1-237369589-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001035.3(RYR2):​c.365G>A​(p.Arg122His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,562,588 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 8.10

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain MIR 1 (size 55) in uniprot entity RYR2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.365G>A	p.Arg122His	missense_variant	6/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.365G>A	p.Arg122His	missense_variant	6/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.365G>A	p.Arg122His	missense_variant	6/106			ENSP00000499787
RYR2	ENST00000659194.3	c.365G>A	p.Arg122His	missense_variant	6/105			ENSP00000499653
RYR2	ENST00000609119.2	c.365G>A	p.Arg122His	missense_variant, NMD_transcript_variant	6/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1410476 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 696422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Aug 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 122 of the RYR2 protein (p.Arg122His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 30847666, 30975432, 31112425). ClinVar contains an entry for this variant (Variation ID: 165069). 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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 26, 2013

The Arg122His variant in RYR2 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational analyses (bioch emical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugg est that this variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. In summary, additional information is needed to fully assess the clinical significance of this variant. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 15, 2023

This missense variant replaces arginine with histidine at codon 122 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 homozygosity in an individual affected with idiopathic ventricular fibrillation and resuscitated sudden cardiac death ((PMID: 29568272, 30975432). Both parents were heterozygous and asymptomatic exhibiting no obvious cardiac pathological phenotype. This variant has also been reported in a family and an unrelated individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 31112425, 31231889). This variant has not been identified 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

May 26, 2022

This missense variant replaces arginine with histidine at codon 122 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 homozygosity in an individual affected with idiopathic ventricular fibrillation and resuscitated sudden cardiac death ((PMID: 29568272, 30975432). Both parents were heterozygous and asymptomatic exhibiting no obvious cardiac pathological phenotype. This variant has also been reported in a family and an unrelated individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 31112425, 31231889). This variant has not been identified 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

Oct 28, 2022

The p.R122H variant (also known as c.365G>A), located in coding exon 6 of the RYR2 gene, results from a G to A substitution at nucleotide position 365. The arginine at codon 122 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as homozygous in an individual with concerns for catecholaminergic polymorphic ventricular tachycardia (CPVT); however, it was found to be inherited from her asymptomatic parents (Bianchi B et al. Front Physiol, 2018 Mar;9:177). Additionally, this alteration has been detected in CPVT cohorts; however, clinical details were limited (Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424; Franciosi S et al. J Cardiovasc Electrophysiol, 2019 10;30:1923-1929; Giudicessi JR et al. Circ Genom Precis Med, 2019 05;12:e002510). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.75		Loss of methylation at R122 (P = 0.0742);.;
MVP		0.95
MPC		0.91
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.48
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: rs727503396; hg19: chr1-237532889; COSMIC: COSV63664819;