rs1415931588

Positions:

• chr1-237377426-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001035.3(RYR2):​c.567A>T​(p.Glu189Asp) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.149

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 13 ACMG points.

• PS1: Transcript NM_001035.3 (RYR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2707246
• PM1: In a domain MIR 2 (size 45) in uniprot entity RYR2_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) 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, 0.918
• PP5: Variant 1-237377426-A-T is Pathogenic according to our data. Variant chr1-237377426-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 463608.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-237377426-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.567A>T	p.Glu189Asp	missense_variant	8/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.567A>T	p.Glu189Asp	missense_variant	8/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.567A>T	p.Glu189Asp	missense_variant	8/106
RYR2	ENST00000659194.3	c.567A>T	p.Glu189Asp	missense_variant	8/105
RYR2	ENST00000609119.2	c.567A>T	p.Glu189Asp	missense_variant, NMD_transcript_variant	8/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2017

In summary, this variant is a rare missense change that has been reported in affected individuals and has been shown to disrupt protein function. This evidence indicates that this variant is pathogenic, but additional data is needed to prove this conclusively. For these reasons, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change enhances the basal activity of RYR2 and increases the fractional calcium release (PMID: 20676041, 22374134). This variant has been reported in the literature in two individuals from one family affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 20676041), and in at least one other unrelated affected individual (PMID: 19926015, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 189 of the RYR2 protein (p.Glu189Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	0.82	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;.
Polyphen		0.98	D;.
Vest4		0.90
MutPred		0.83		Loss of disorder (P = 0.2229);.;
MVP		0.99
MPC		0.80
ClinPred		0.99	D
GERP RS		-5.1
Varity_R		0.73
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1415931588; hg19: chr1-237540726;