rs794728802

Positions:

• chr1-237806236-A-C
• chr1-237806236-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000366574.7(RYR2):​c.14251A>C​(p.Lys4751Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4751E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 ENST00000366574.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.29

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237806236-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 463577.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.879
• PP5: Variant 1-237806236-A-C is Pathogenic according to our data. Variant chr1-237806236-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14251A>C	p.Lys4751Gln	missense_variant	99/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14251A>C	p.Lys4751Gln	missense_variant	99/105	1	NM_001035.3	ENSP00000355533	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2014

p.Lys4751Gln (AAG>CAG): c.14251 A>C in exon 99 of the RYR2 gene (NM_001035.2). The K4751Q mutation in the RYR2 gene has been reported in one Japanese individual diagnosed with CPVT and atrial flutter (Kawamura M et al., 2013). K4751Q is a semi-conservative amino acid substitution as these residues share similar properties, but differs in size, charge, or other properties which may impact secondary structure. K4751Q occurs at a position that is conserved across species and is located in the channel region, which is a known hotspot for mutations (Medeiros-Domingo A et al, 2009). Mutations in nearby residues (H4742Y, H4762P) have been reported in association with sudden cardiac death and CPVT, respectively, further supporting the functional importance of this region of the protein. In silico analysis predicts that K4751Q is probably damaging to protein structure/function. Additionally, the K4751Q mutation was not observed inapproximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, K4751Q in the RYR2 gene is interpreted as a disease-causing mutation. The variant is found in CPVT panel(s). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2017

The p.K4751Q variant (also known as c.14251A>C), located in coding exon 99 of the RYR2 gene, results from an A to C substitution at nucleotide position 14251. The lysine at codon 4751 is replaced by glutamine, an amino acid with similar properties. This alteration (reported as c.14251A>C, p.K4750Q) has been previously reported as de novo in an individual with a clinical diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) (Kawamura M et al. Circ J. 2013;77:1705-13; Uehara A et al. J. Gen. Physiol., 2017 Feb;149:199-218). Limited in vitro functional studies demonstrated effects on gating kinetics in transfected cells (Uehara A et al. J. Gen. Physiol., 2017 Feb;149:199-218). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.45		Loss of methylation at K4751 (P = 0.0083);.;
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs794728802; hg19: chr1-237969536;