rs794728746

Positions:

• chr1-237638480-G-A
• chr1-237638480-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000366574.7(RYR2):​c.6916G>A​(p.Val2306Ile) 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. V2306F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 ENST00000366574.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.99

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 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000366574.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237638480-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2101383.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, 0.96
• PP5: Variant 1-237638480-G-A is Pathogenic according to our data. Variant chr1-237638480-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237638480-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.6916G>A	p.Val2306Ile	missense_variant	45/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.6916G>A	p.Val2306Ile	missense_variant	45/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.6916G>A	p.Val2306Ile	missense_variant	45/106			ENSP00000499787
RYR2	ENST00000659194.3	c.6916G>A	p.Val2306Ile	missense_variant	45/105			ENSP00000499653
RYR2	ENST00000609119.2	c.6916G>A	p.Val2306Ile	missense_variant, NMD_transcript_variant	45/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 03, 2021

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Furthermore, this variant occurs within one of the three regions of the RYR2 gene (N-terminal domain) where other pathogenic variants have been reported to cluster (PMID: 19926015). In summary, this missense variant is absent from population databases, is predicted to be deleterious, and has been reported in affected patients as the result of a de novo events. For these reasons, this variant has been classified as Pathogenic. This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) and an individual that suffered a cardiac arrest (PMID: 14571276 and Invitae database). In both cases this variant presumably occurred as a de novo mutational event. ClinVar contains an entry for this variant (Variation ID: 201387). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 2306 of the RYR2 protein (p.Val2306Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.91	N;.
REVEL	Pathogenic	0.83
Sift	Benign	0.061	T;.
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.85		Loss of sheet (P = 0.1398);.;
MVP		0.97
MPC		1.0
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.20
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs794728746; hg19: chr1-237801780;