rs373665895

Variant names:

• chr1-237530432-T-C
• rs373665895
• NM_001035.3:c.2828T>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP3 BS1_Supporting BS2

The NM_001035.3(RYR2):​c.2828T>C​(p.Leu943Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000163 in 1,605,904 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 4.87

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 -3 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, 0.795
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000854 (13/152214) while in subpopulation NFE AF= 0.000147 (10/68030). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in gnomad4. There are 5 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 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.2828T>C	p.Leu943Ser	missense_variant	Exon 25 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.2828T>C	p.Leu943Ser	missense_variant	Exon 25 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.2828T>C		non_coding_transcript_exon_variant	Exon 25 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.2828T>C	p.Leu943Ser	missense_variant	Exon 25 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.2828T>C	p.Leu943Ser	missense_variant	Exon 25 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000105 AC: 25 AN: 237416 Hom.: 0 AF XY: 0.000125 AC XY: 16 AN XY: 128056

Gnomad AFR exome AF: 0.0000692

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000171 AC: 249 AN: 1453690 Hom.: 0 Cov.: 30 AF XY: 0.000170 AC XY: 123 AN XY: 721994

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Aug 16, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Jan 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with hypertrophic cardiomyopathy, atrioventricular nodal reentry tachycardia (AVNRT), sudden infant death syndrome (SIDS), and CPVT (PMID: 25351510, 32508047, 28074886, 28404607, 29396561); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); 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: 31112425, 32508047, 19926015, 28404607, 25351510, 28074886, 32152366, 29396561) -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Dec 18, 2023

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 leucine with serine at codon 943 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 31112425), in two individuals affected with atrioventricular nodal reentry tachycardia (PMID: 29396561, 32508047), in one individual affected with hypertrophic cardiomyopathy (PMID: 25351510), and in one infant with sudden death (PMID: 32152366). This variant occurs at an elevated frequency in the general population and has been identified in 30/268806 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

Apr 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with serine at codon 943 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 31112425), in two individuals affected with atrioventricular nodal reentry tachycardia (PMID: 29396561, 32508047), in one individual affected with hypertrophic cardiomyopathy (PMID: 25351510), and in one infant with sudden death (PMID: 32152366). This variant occurs at an elevated frequency in the general population and has been identified in 30/268806 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;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR2 NM_001035.2 exon 25 p.Leu943Ser (c.2828T>C): This variant has been reported in the literature in one individual with HCM (Lopes 2015 PMID:25351510). This variant is also present in 0.01% (22/122756) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-237693732-T-C) and is present in ClinVar (Variation ID:201232). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 943 of the RYR2 protein (p.Leu943Ser). This variant is present in population databases (rs373665895, gnomAD 0.02%). This missense change has been observed in individual(s) with atrioventricular nodal reentry tachycardia, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and/or sudden infant death (PMID: 25351510, 28074886, 29396561, 31112425, 32152366). ClinVar contains an entry for this variant (Variation ID: 201232). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. 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. -

Cardiovascular phenotype Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L943S variant (also known as c.2828T>C), located in coding exon 25 of the RYR2 gene, results from a T to C substitution at nucleotide position 2828. The leucine at codon 943 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy, whole exome sequencing, atrioventricular nodal reentry tachycardia, sudden death, and catecholaminergic polymorphic ventricular tachycardia cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; Neubauer J et al. Eur J Hum Genet. 2017 Apr;25(4):404-409; Andreasen L et al. Eur J Hum Genet, 2018 05;26:660-668; Giudicessi JR et al. Circ Genom Precis Med, 2019 05;12:e002510). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Nov 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.2828T>C (p.Leu943Ser) results in a non-conservative amino acid change located in the Ryanodine receptor, Ryr domain (IPR003032) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 237416 control chromosomes. The observed variant frequency is approximately 3.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.2828T>C has been reported in the literature as a VUS in settings of multigene panel testing in cohorts of individuals with a variety of cardiac conditions such as SIDS/Atrioventricular nodal reentry tachycardia (AVNRT) (example, Neubauer_2017, Giudicessi_2019, Olubando_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.
Polyphen		0.081	B;.
Vest4		0.85
MVP		0.69
MPC		0.51
ClinPred		0.52	D
GERP RS		5.2
Varity_R		0.65
gMVP		0.90

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: rs373665895; hg19: chr1-237693732;