1-237377386-G-T

Position:

• chr1-237377386-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001035.3(RYR2):​c.527G>T​(p.Arg176Leu) 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. R176Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237377386-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.932
• PP5: Variant 1-237377386-G-T is Pathogenic according to our data. Variant chr1-237377386-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201195.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.527G>T	p.Arg176Leu	missense_variant	8/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.527G>T	p.Arg176Leu	missense_variant	8/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.527G>T		non_coding_transcript_exon_variant	8/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.527G>T	p.Arg176Leu	missense_variant	8/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.527G>T	p.Arg176Leu	missense_variant	8/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: 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

GeneDx

Oct 24, 2024

Identified in a large Newfoundland family with index cases experiencing catecholaminergic polymorphic ventricular tachycardia (CPVT) or sudden cardiac arrest (Lauson et al. (2014) http://www.ashg.org/2014meeting/abstracts/fulltext/f140122642.htm); extensive family genotyping and phenotyping revealed numerous carriers who were asymptomatic or had a history of syncope, indicating substantial phenotypic variability and lower than previously reported penetrance (PMID: 31994352); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34760626, 19926015, 31994352, 35135837) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2016

The p.R176L variant (also known as c.527G>T), located in coding exon 8 of the RYR2 gene, results from a G to T substitution at nucleotide position 527. The arginine at codon 176 is replaced by leucine, an amino acid with dissimilar properties. Although the p.R176L variant has not been reported previously, another alteration at the same position in RYR2, p.R176Q, has been identified in multiple individuals with arrhythmias (Tester DJ et al. Heart Rhythm. 2005;2(10):1099-105; Haugaa KH et al. Europace. 2010;12(3):417-23; Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54(22):2065-74). Furthermore, this alteration has been reported as occurring in a disease-associated hotspot loop of the RYR2 protein (Amador FJ et al. Proc Natl Acad Sci U.S.A. 2009;106(27):11040-4). The RYR2 p.R176L variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6101 samples (12202 alleles) with coverage at this position. This amino acid position is completely 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	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.
Polyphen		0.10	B;.
Vest4		0.86
MutPred		0.68		Loss of disorder (P = 0.0508);.;
MVP		0.94
MPC		0.45
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.84

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: rs794728708; hg19: chr1-237540686;