chr1-237784887-A-G

Variant names:

• chr1-237784887-A-G
• rs753733164
• NM_001035.3:c.13175A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_001035.3(RYR2):​c.13175A>G​(p.Lys4392Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000093 in 1,613,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (3 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 3.71
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 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, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33532923).
• BP6: Variant 1-237784887-A-G is Benign according to our data. Variant chr1-237784887-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 575869.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000592 (9/152112) while in subpopulation EAS AF = 0.00174 (9/5166). AF 95% confidence interval is 0.000909. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.13175A>G	p.Lys4392Arg	missense_variant	Exon 90 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13175A>G	p.Lys4392Arg	missense_variant	Exon 90 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.13199A>G	p.Lys4400Arg	missense_variant	Exon 91 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*4267A>G		non_coding_transcript_exon_variant	Exon 89 of 104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*4267A>G		3_prime_UTR_variant	Exon 89 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152112 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: 0.00174

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246870 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461068 Hom.: 3 Cov.: 33 AF XY: 0.0000798 AC XY: 58 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00348 AC: 138 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111592

Other (OTH) AF: 0.0000331 AC: 2 AN: 60352

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000827 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1 Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated Japanese affected with catecholaminergic polymorphic ventricular tachycardia, as well as in a few asymptomatic carriers in their families (PMID: 23595086, 25092222). This variant has also been reported in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930). This variant has been identified in 4/246870 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 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces lysine with arginine at codon 4392 in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with catecholaminergic polymorphic ventricular tachycardia, as well as in a few asymptomatic carriers in their families (PMID: 23595086, 25092222). This variant has also been reported in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930). This variant has been identified in 4/246870 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.

not provided Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular phenotype Uncertain:1

Mar 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K4392R variant (also known as c.13175A>G), located in coding exon 90 of the RYR2 gene, results from an A to G substitution at nucleotide position 13175. The lysine at codon 4392 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in the heterozygous state in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and in asymptomatic relatives (Arakawa J et al. Heart Vessels, 2015 Nov;30:835-40; Kawata H et al. Circ J, 2016 Aug;80:1907-15; Kawamura M et al. Circ J, 2013 Apr;77:1705-13). This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not specified Benign:1

May 16, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.13175A>G (p.Lys4392Arg) results in a conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 324312 control chromosomes, including 2 homozygotes (gnomAD and jMorp databases (Tadaka_2021)). The observed variant frequency is approximately 41.62 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.13175A>G has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia, however, the variant was also identified in unaffected individuals and found to not segregate with disease among related individuals (e.g., Kawamura_2013, Arakawa_2015). Additionally, in one proband with catecholaminergic polymorphic ventricular tachycardia, a co-occurrence with another pathogenic variant was reported (RYR2 c.12006G>A, p.M4002I; Kawamura_2013), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant showed no damaging effect on the cytosolic calcium-dependent activity of RYR2 (e.g., Kurebayashi_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25092222, 23595086, 35446340, 33179747). Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: 3 submitters classified the variant as uncertain significance, and one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as benign.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.26
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.85	T;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		3.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.40	N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.57	T;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.71
ClinPred		0.052	T
GERP RS		3.5
Varity_R		0.050
gMVP		0.24
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs753733164; hg19: chr1-237948187;