1-237639110-G-A

Position:

• chr1-237639110-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001035.3(RYR2):​c.7024G>A​(p.Gly2342Arg) 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. G2342E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.00

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]

RYR2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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, 0.888
• PP5: Variant 1-237639110-G-A is Pathogenic according to our data. Variant chr1-237639110-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519356.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7024G>A	p.Gly2342Arg	missense_variant	46/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7024G>A	p.Gly2342Arg	missense_variant	46/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.7024G>A		non_coding_transcript_exon_variant	46/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.7024G>A	p.Gly2342Arg	missense_variant	46/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.7024G>A	p.Gly2342Arg	missense_variant	46/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2017

The p.G2342R variant (also known as c.7024G>A), located in coding exon 46 of the RYR2 gene, results from a G to A substitution at nucleotide position 7024. The glycine at codon 2342 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in an individual with catecholaminergic polymorphic ventricular tachycardia, and suggested to be mosaic in the proband's clinically asymptomatic father (Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517). This variant was also detected in a case of sudden death, and a family member carrying this alteration was described as clinically asymptomatic with frequent premature ventricular beats on exercise testing despite beta-blockers (Cann F et al. Clin. Genet., 2016 Mar;). 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	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.3	D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.46		Gain of methylation at G2342 (P = 0.024);.;
MVP		0.86
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.94

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: rs1553263907; hg19: chr1-237802410;