1-237454494-C-G

Variant names:

• chr1-237454494-C-G
• rs376612295
• NM_001035.3:c.1396C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2 PP3_Moderate BS1_Supporting BS2

The NM_001035.3(RYR2):​c.1396C>G​(p.Pro466Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P466Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 7.90

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.88
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000592 (9/152074) while in subpopulation NFE AF= 0.000132 (9/68004). AF 95% confidence interval is 0.0000681. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1396C>G	p.Pro466Ala	missense_variant	Exon 15 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1396C>G	p.Pro466Ala	missense_variant	Exon 15 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1396C>G		non_coding_transcript_exon_variant	Exon 15 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1396C>G	p.Pro466Ala	missense_variant	Exon 15 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.1396C>G	p.Pro466Ala	missense_variant	Exon 15 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000105 AC: 26 AN: 248716 Hom.: 0 AF XY: 0.0000815 AC XY: 11 AN XY: 134904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461334 Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35 AN XY: 726938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with aborted cardiac arrest and a family history of multiple people with sudden cardiac death (Tester et al., 2005); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 161383; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 32048431, 25637381, 23861362, 19926015, 24025405, 28404607, 16188589, 27538377, 29555771, 31980526, 33825858) -

Polymorphic ventricular tachycardia Uncertain:2

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 466 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experiment has shown that this variant has no impact on caffeine-induced calcium release in cultured cells (PMID: 33825858). However, the clinical relevance of this observation is not known. This variant has been reported in a young individual with aborted cardiac arrest and a family history of sudden cardiac death (PMID: 16188589), in an individual with a cardiomyopathy diagnosis (PMID: 32009526), and in an infant with recurrent apparent life-threatening event followed by sudden cardiac death (Hernandez et al., 2016). This variant has also been identified in 28/280104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Feb 22, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 466 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experiment has shown that this variant has no impact on caffeine-induced calcium release in cultured cells (PMID: 33825858). However, the clinical relevance of this observation is not known. This variant has been reported in a young individual with aborted cardiac arrest and a family history of sudden cardiac death (PMID: 16188589), in an individual with a cardiomyopathy diagnosis (PMID: 32009526), and in an infant with recurrent apparent life-threatening event followed by sudden cardiac death (Hernandez et al., 2016). This variant has also been identified in 28/280104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 466 of the RYR2 protein (p.Pro466Ala). This variant is present in population databases (rs376612295, gnomAD 0.03%). This missense change has been observed in individual(s) with aborted cardiac arrest or catecholaminergic polymorphic ventricular tachycardia (PMID: 16188589, 28404607, 29555771, 32009526, 32152366). ClinVar contains an entry for this variant (Variation ID: 161383). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RYR2 function (PMID: 33825858). 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. -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P466A variant (also known as c.1396C>G), located in coding exon 15 of the RYR2 gene, results from a C to G substitution at nucleotide position 1396. The proline at codon 466 is replaced by alanine, an amino acid with highly similar properties. This variant has been reported in a number of individuals with a variety of cardiac disease phenotypes, including cardiac arrest, left ventricular hypertrophy, and ventricular tachycardia (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). However, this variant has also been reported in exome cohorts (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D;.
Polyphen		0.98	D;.
Vest4		0.89
MVP		0.98
MPC		0.76
ClinPred		0.24	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs376612295; hg19: chr1-237617794;