chr1-237387353-A-G

Position:

• chr1-237387353-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_001035.3(RYR2):​c.649A>G​(p.Ile217Val) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,613,984 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). Synonymous variant affecting the same amino acid position (i.e. I217I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 6.32

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001035.3
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26167762).
• BP6: Variant 1-237387353-A-G is Benign according to our data. Variant chr1-237387353-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5, Benign=1}. Variant chr1-237387353-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.649A>G	p.Ile217Val	missense_variant	9/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.649A>G	p.Ile217Val	missense_variant	9/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.649A>G		non_coding_transcript_exon_variant	9/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.649A>G	p.Ile217Val	missense_variant	9/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.649A>G	p.Ile217Val	missense_variant	9/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000161 AC: 40 AN: 249166 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135176

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

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: 0.000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1461686 Hom.: 0 Cov.: 30 AF XY: 0.000261 AC XY: 190 AN XY: 727124

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

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: 0.000326

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74470

Gnomad4 AFR AF: 0.000120

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: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000388 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 07, 2017	p.Ile217Val (c.649A>G) in exon 9 of the RYR2 gene (NM_001035.2; ENST00000366574; chr1-237550653-A-G) SCICD Classification: variant of uncertain significance, likely benign based on high prevalence in some ethnic groups. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Disease-causing variants in RYR2 are the cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Exon-level evidence: Disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959) (Yano et al. 2006). This variant is located within the N-terminal domain. Deletions of exon 3 have previously been reported in association with CPVT in at least 5 unrelated families with very strong segregation data and functional data (Bhuiyan et al. 2007, Marjamaa et al. 2009, Medeiros-Domingo et al. 2009, Kawamura et al. 2013, Lobo et al. 2011, Tang et al., 2012). Region-level evidence: This variant is located in a region of RYR2 in which the amount of variation in controls is significantly higher than the amount of variation in cases (Amr et al. 2016). Case data (not including our patient): at least 11 individuals (ARVC, unexplained cardiac arrest, unselected) ClinVar: this variant has been submitted by 5 other labs with conflicting interpretations of pathogenicity LMM (VUS): seen in 2 Caucasian patients: one with sudden cardiac death and another with restricted cardiomyopathy. This variant did not segregate with disease in the RCM family. Redundant with Tester 2012. ClinSeq/NIH (likely benign) EGL (likely benign) GeneDx (likely benign) Oregon Health and Sciences University (VUS) Cases in the literature: Tester et al. 2012: 1/173 cases of SCD. Patient was a 21yo male who syncopized prior to SCD. He had a family history of SCD. He had two other variants in RYR2 that are ?classification. Redundant with LMM's case. Ng et al 2017: Present in 1/870 individuals who underwent whole exome sequencing. They were not selected for inherited cardiovascular disease. Sanchez-Molero et al. 2016: Present in 1/798 forensic cases who died suddenly and whose death remained unexplained. Landstrom et al. 2017: 1/6517 individuals who underwent whole exome sequencing at a clinical laboratory. These patients were not selected for cardiovascular disease. Medeiros-Domingo et al 2017: 1/14 unrelated individuals who underwent WES for ARVC. 70yo male with definite ARVC. Had another variant in DSG2 (pathogenicity f this variant not evaluated). Segregation data: 1 family, 2 individuals, did not segregate (LMM). Functional data: none In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align- GVGD: "Class C25")." Conservation data: The isoleucine at codon 217 is completely conserved across mammals, but not all species. Neighboring amino acids are also well conserved. Nearby pathogenic variants at this codon or neighboring codons: Per ClinVar, a variant at a nearby codon, Q2200E, is classified as likely pathogenic. Population data: Highest MAF in individuals of European descent = 0.036%. The variant was reported online in 48 of 138,532 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 45 of 63,294 individuals of Eurpean descent (MAF=0.035%), 2 of 12,007 individuals of African descent and 1 of 17,209 individuals of Latino descent. The phenotype of those individuals -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	Reported in association sudden unexplained death, hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) in the published literature; however, some probands were found to harbor additional cardiogenetic variants (Tester et al., 2012; Medeiros-Domingo et al., 2016; Sanchez et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; 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: 25925909, 24025405, 22677073, 25372681, 27930701, 27153395, 27194543, 27538377, 28404607, 33232181, 28988457, 33825858, Olubando2020, 29511324) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2016	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2024	Variant summary: RYR2 c.649A>G (p.Ile217Val) results in a conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor (IPR014821) domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249166 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05). c.649A>G has been reported in the literature in individuals affected with a variety of cardiac phenotypes such as syncope, HCM, ARVC, and arrythmogenic cardiomyopathy (Tester_2012, Sanchez_2016, Medeiros-Domingo_2017, Mates_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (MYBPC3, c.2309-2A>G, diagnostic of HCM), providing supporting evidence for a benign role. At least one publication reports experimental evidence that this variant exhibited a caffeine response similar to wildtpe (e.g. Zhong_2021), however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 29511324, 27194543, 27930701, 22677073, 33825858). ClinVar contains an entry for this variant (Variation ID: 165072). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2015	The p.Ile217Val variant in RYR2 has been reported in 1 Caucasian individual who succumbed to SCD (Tester 2012) and was identified by our laboratory in 1 Caucasi an adult with RCM and did not segregate with disease in 1 affected relative. Thi s variant has been identified in 17/66726 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200642525). Isoleucine (Ile) is not conserved in evolutionarily distant species and the cha nge to valine (Val) is present in Mexican tetra and lamprey. Additional computat ional prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ile217Val variant i s uncertain. -

Cardiomyopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 02, 2017	- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 14, 2019	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 14, 2019	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	D;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.93	L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.20	N;.
REVEL	Uncertain	0.49
Sift	Benign	0.86	T;.
Polyphen		0.11	B;.
Vest4		0.32
MVP		0.85
MPC		0.33
ClinPred		0.047	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.50

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: rs200642525; hg19: chr1-237550653;