rs764698152

chr1-237445470-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_001035.3(RYR2):c.1240C>T(p.Arg414Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,726 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. R414H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 6.07

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001035.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237445471-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 1-237445470-C-T is Pathogenic according to our data. Variant chr1-237445470-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201212.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=3, Likely_pathogenic=1}. Variant chr1-237445470-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.1240C>T	p.Arg414Cys	missense_variant	14/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.1240C>T	p.Arg414Cys	missense_variant	14/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.1240C>T	p.Arg414Cys	missense_variant	14/106
RYR2	ENST00000659194.3	c.1240C>T	p.Arg414Cys	missense_variant	14/105
RYR2	ENST00000609119.2	c.1240C>T	p.Arg414Cys	missense_variant, NMD_transcript_variant	14/104	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.00000890 AC: 13 AN: 1461440 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

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 15, 2016	A variant of uncertain significance has been identified in the RYR2 gene.The R414C variant was previously published in a 16-year-old female who died while swimming competitively, and it was absent from 400 controls (Creighton et al., 2006). The R414C variant was subsequently reported in a 10-year-old boy who was experiencing ventricular fibrillation during a swimming race (Moray et al., 2011). The R414C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R414C 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. The R414C variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to arginine are tolerated across species. While another variant at this same residue (R414L) and variants in nearby residues (S406L, R407S, S413T, T415R, I419F) have been reported in HGMD in association with CPVT (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Finally, the R414C variant is classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000230388.1; Landrum et al., 2016). -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 414 of the RYR2 protein (p.Arg414Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant RYR2-related conditions (PMID: 15887426, 21478052; Invitae). ClinVar contains an entry for this variant (Variation ID: 201212). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect RYR2 function (PMID: 23152493). This variant disrupts the p.Arg414 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 15466642, 16188589), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 22, 2020

This missense variant replaces arginine with cysteine at codon 414 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental study has shown that this variant does not affect the calcium sensitivity of RYR2 channels (PMID: 23152493). This variant has been reported in two unrelated individuals affected with sudden cardiac death (PMID: 15887426, 21478052). This variant has also been reported in a healthy parent of one of the two probands, who had no history of cardiac arrhythmias (PMID: 21478052). 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

Jul 21, 2017

The p.R414C variant (also known as c.1240C>T), located in coding exon 14 of the RYR2 gene, results from a C to T substitution at nucleotide position 1240. The arginine at codon 414 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in a ten year old boy with ventricular fibrillation during swimming, as well as in the boy's reportedly healthy mother (Moray A et al. Heart Lung Circ, 2011 Nov;20:731-3). This alteration was also reported in an individual who experienced sudden cardiac death at age sixteen while swimming (Tester DJ et al. Mayo Clin Proc 2005;80(5):596-600; Creighton et al. J Mol Diagn. 2006;8(1):62-7). Another alteration affecting this amino acid (p.R414L) has also been reported in association with drowning (Choi G. Circulation. 2004;110(15):2119-24). This amino acid position is well 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	Benign	0.25
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.82		Loss of MoRF binding (P = 0.0076);.;
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.58
gMVP		0.66

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: rs764698152; hg19: chr1-237608770; COSMIC: COSV63693384;