rs794728712

chr1-237388137-G-Achr1-237388137-G-C

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.727G>A(p.Glu243Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,564 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E243G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.05

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 3 (size 55) in uniprot entity RYR2_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.727G>A	p.Glu243Lys	missense_variant	10/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.727G>A	p.Glu243Lys	missense_variant	10/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.727G>A	p.Glu243Lys	missense_variant	10/106
RYR2	ENST00000659194.3	c.727G>A	p.Glu243Lys	missense_variant	10/105
RYR2	ENST00000609119.2	c.727G>A	p.Glu243Lys	missense_variant, NMD_transcript_variant	10/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461564 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2018

The E243K variant in the RYR2 gene has been reported in one individual with definitive CPVT and one individual with either strong or possible CPVT (Hayashi et al., 2009; Medeiros-Domingo et al., 2009). The E243K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E243K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The E243K variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense mutations occur (Medeiros-Domingo et al., 2009). Although this region is not a channel functional domain and there are no nearby definitively pathogenic variants, a handful of individuals identified by GeneDx to harbor this variant reported syncope and/or sudden cardiac arrest and at least one individual had syncope with exertion, suggesting that this variant may be pathogenic, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Furthermore, no individual carrying this variant reported a clearly strong clinical diagnosis of CPVT or ARVC, and some individuals harbored additional cardiogenetic variants of uncertain significance. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 201200). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) or RYR2-related clinical features (PMID: 19398665, 19926015, 21954897, 29453246). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 243 of the RYR2 protein (p.Glu243Lys). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2016

The p.E243K variant (also known as c.727G>A), located in coding exon 10 of the RYR2 gene, results from a G to A substitution at nucleotide position 727. The glutamic acid at codon 243 is replaced by lysine, an amino acid with similar properties. This variant has been described in association with catecholaminergic polymorphic ventricular tachycardia (CPVT) and exertional syncope (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54:2065-74; Hayashi M et al. Circulation. 2009;119:2426-34). This variant was previously reported in the SNPDatabase as rs794728712, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6265 samples (12530 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;.
Polyphen		0.98	D;.
Vest4		0.88
MutPred		0.87		Gain of methylation at E243 (P = 4e-04);.;
MVP		0.93
MPC		0.78
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.79

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: rs794728712; hg19: chr1-237551437; COSMIC: COSV105920921;