rs1553322892

chr1-237784231-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001035.3(RYR2):c.12519A>G(p.Ile4173Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.362

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.12519A>G	p.Ile4173Met	missense_variant	90/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.12519A>G	p.Ile4173Met	missense_variant	90/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.12540A>G	p.Ile4180Met	missense_variant	91/106
RYR2	ENST00000659194.3	c.12507A>G	p.Ile4169Met	missense_variant	90/105
RYR2	ENST00000609119.2	c.*3611A>G		3_prime_UTR_variant, NMD_transcript_variant	89/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 27, 2017

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 520468). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 4173 of the RYR2 protein (p.Ile4173Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	N;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D;.
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.43		Gain of disorder (P = 0.0268);.;
MVP		0.92
MPC		1.9
ClinPred		0.97	D
GERP RS		-1.6
Varity_R		0.23
gMVP		0.80

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: rs1553322892; hg19: chr1-237947531; COSMIC: COSV63710113;