chr1-237657959-G-T

Position:

• chr1-237657959-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001035.3(RYR2):​c.8145G>T​(p.Glu2715Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,512,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1 O:1
• Conservation: PhyloP100: 1.01

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 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.
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.8145G>T	p.Glu2715Asp	missense_variant	54/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.8145G>T	p.Glu2715Asp	missense_variant	54/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.8145G>T	p.Glu2715Asp	missense_variant	54/106			ENSP00000499787
RYR2	ENST00000659194.3	c.8145G>T	p.Glu2715Asp	missense_variant	54/105			ENSP00000499653
RYR2	ENST00000609119.2	c.8145G>T	p.Glu2715Asp	missense_variant, NMD_transcript_variant	54/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000250

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000104 AC: 14 AN: 134624 Hom.: 0 AF XY: 0.0000982 AC XY: 7 AN XY: 71280

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.000274

GnomAD4 exome AF: 0.000143 AC: 194 AN: 1359994 Hom.: 0 Cov.: 25 AF XY: 0.000137 AC XY: 92 AN XY: 670584

Gnomad4 AFR exome AF: 0.0000671

Gnomad4 AMR exome AF: 0.000132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000159

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74352

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000283 AC: 1

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.0000407 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 14, 2017	p.Glu2715Asp (c.8145G>T; chr1:237657959) in the RYR2 gene (NM_001035.2) Given the lack of association between RYR2 and Brugada syndrome, the weak case data and its frequency in the general population, 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"). We've seen this variant in 1 patient with Brugada syndrome in our clinic. Testing was done at Invitae. The RYR2 gene is associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). It has not been associated with Brugada syndrome. There is no case data available on this variant. One paper mentions this variant (Ng et al 2013), in a study that performed exome sequencing on 870 participants not selected for arrhythmia, cardiomyopathy or family history of sudden death. Its purpose was to uncover the potential for incidental findings of inherited cardiovascular diseases on exome sequencing ordered on patients of other reasons. The p.Glu2715Asp variant was found in 1 of 870 of these individuals. Ng and colleagues interpret this variant as being too common in the NHLBI exome sequencing project (MAF=0.1%) compared to the incidence of CPVT (1 in 10,000). This variant is present in ClinVar, with conflicting interpretations: GeneDx, Invitae and Blueprint Genetics all classify this variant as a variant of uncertain significance. The Biesecker Lab at the NIH classifies this variant as likely benign. This variant is not located in the three hot-spot regions in which pathogenic variants in RYR2 cluster. This variant is located within a region of the RYR2 gene which is tolerant to missense variation (Amr et al 2016). Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. The glutamine at codon 2715 is completely conserved across species, as are neighboring amino acids. There are no other pathogenic/likely pathogenic variants listed in ClinVar at nearby codons. The variant was reported online in 22 of 80,578 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 15 of 33,604 individuals of European descent (MAF=0.02%), 3 of 9,357 individuals of Latino descent and 2 of 7,469 individuals of African descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with sudden unexpected death and in a patient with hypertrophic cardiomyopathy (HCM); both of whom harbored additional cardiogenetic variants (PMID: 27930701, 32746448); Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 32268277, 29453246, 32746448, 27930701, 23861362, 19926015) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 12-06-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2715 of the RYR2 protein (p.Glu2715Asp). This variant is present in population databases (rs200420897, gnomAD 0.02%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 27930701, 29453246, 32152366). ClinVar contains an entry for this variant (Variation ID: 180497). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	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 an individual with suspected catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246), two individuals with sudden unexplained death (PMID: 27930701, 32268277), and an individual with suspected coronary artery disease (PMID: 23861362). This variant has been identified in 19/165846 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 01, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 17, 2019

Variant summary: RYR2 c.8145G>T (p.Glu2715Asp) results in a conservative amino acid change located in the Ryanodine receptor Ryr domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 134624 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. c.8145G>T has been reported in the literature in individuals affected with CPVT, BrS and unexplained death. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

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 an individual with suspected catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246), two individuals with sudden unexplained death (PMID: 27930701, 32268277), and an individual with suspected coronary artery disease (PMID: 23861362). This variant has been identified in 19/165846 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. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 25, 2014

- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2022

The p.E2715D variant (also known as c.8145G>T), located in coding exon 54 of the RYR2 gene, results from a G to T substitution at nucleotide position 8145. The glutamic acid at codon 2715 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort and has been reported in a control subject (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This variant was also detected in an arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been reported in pediatric hypertrophic cardiomyopathy (HCM), sudden unexplained death, and catecholaminergic polymorphic ventricular tachycardia (CPVT) cohorts (Kapplinger JD et al. Circ Genom Precis Med, 2018 Feb;11:e001424; Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). This amino acid position is highly conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.50
Sift	Benign	0.22	T;.
Polyphen		0.98	D;.
Vest4		0.38
MutPred		0.36		Gain of sheet (P = 0.1208);.;
MVP		0.92
MPC		1.1
ClinPred		0.30	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200420897; hg19: chr1-237821259; COSMIC: COSV63672270;