rs764396074

Variant names:

• chr1-237709081-A-G
• rs764396074
• NM_001035.3:c.10125A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001035.3(RYR2):​c.10125A>G​(p.Arg3375Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,433,284 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.28
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 1-237709081-A-G is Benign according to our data. Variant chr1-237709081-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235051.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000279 (40/1433284) while in subpopulation NFE AF = 0.0000346 (38/1097500). AF 95% confidence interval is 0.0000257. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.10125A>G	p.Arg3375Arg	synonymous	Exon 69 of 105	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.10125A>G	p.Arg3375Arg	synonymous	Exon 69 of 105	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.10125A>G	p.Arg3375Arg	synonymous	Exon 69 of 106	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*1160A>G		non_coding_transcript_exon	Exon 67 of 104	ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000874 AC: 2 AN: 228944 AF XY: 0.00000803

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000279 AC: 40 AN: 1433284 Hom.: 0 Cov.: 30 AF XY: 0.0000254 AC XY: 18 AN XY: 709962

African (AFR) AF: 0.00 AC: 0 AN: 32090

American (AMR) AF: 0.00 AC: 0 AN: 39594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39264

South Asian (SAS) AF: 0.00 AC: 0 AN: 82378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.0000346 AC: 38 AN: 1097500

Other (OTH) AF: 0.0000339 AC: 2 AN: 59006

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. 61yo Caucasian male with ARVC. Genetic testing: The patient had genetic testing with the GeneDx laboratory with their comprehensive cardiomyopathy panel. This was ordered by his PAMF cardiologist, Dr. Aria Dibiase. The test included 77 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1) Results reported on June 9th, 2015 showed the following variants were found (see report below): -p.Glu102Lys (c.304G>A) in the DSC2 gene (NM_024422.3) -p.Arg3375Arg (c.10125A>G) in the RYR2 gene (NM_001035.2) -p.Ala551Val (c.1652C>T) in the LAMA4 gene (NM_002290.3) These variants are reviewed in detail below. They are all inconclusive. The DSC2 variant is likely too common to cause ARVC. There is minimal data available on the other two genes. Given the large number of genes included on this panel and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and several rare variants found with this test. As a result it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have. p.Glu102Lys (c.304G>A) in the DSC2 gene (NM_024422.3) GeneDx classifies this variant as a "variant, likely disease causing", which, per prior discussion with them, is equivalent to a variant of uncertain significance, probably disease causing. Given the variant has been observed in disparate phenotypes and is present with an MAF >0.1% in samples unselected for ARVC, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the GeneDx report and the LMM ClinVar entry, the variant has been reported in the literature in at least 5 individuals with ARVC (Beffagna 2007, De Bertoli et al 2010, Quarta 2011, Anastasakis 2012). Assertions in ClinVar are conflicting with variant of uncertain significance (LMM, Blueprint), likely benign (CSER), likely pathogenic (GeneDx). In their ClinVar submission, LMM notes that they have observed this variant in 6 individuals with varied phenotypes: "1 with SCA, 1 with HCM, 1 with ARVC and 3 with DCM (1 of whom carries likely pathogenic variant in MYBPC3)." p.Arg3375Arg (c.10125A>G) in the RYR2 gene (NM_001035.2) Given The lack of case data and unclear role of variants of this type in this gene, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant appears to be novel. The variant is predicted to create a cryptic splice donor site in exon 69 that is predicted to cause abnormal gene splicing. However, they note that only one splice variant in RYR2 is reported in HGMD in association with CPVT. There are only four splicing variants in RYR2 in ClinVar. Three are noted as variant

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 3375 of the RYR2 protein. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/228944 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

Jul 12, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 235051; Landrum et al., 2016)

Cardiomyopathy Benign:1

Dec 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Dec 11, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.64
PhyloP100		1.3
PromoterAI		0.0065	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs764396074; hg19: chr1-237872381;