rs397516510

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PM1PM2PM5PP2PP3_StrongPP5BS2

The NM_001035.3(RYR2):c.13528G>A(p.Ala4510Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,420,270 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4510V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity RYR2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001035.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-237791480-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. GenCC has associacion of the gene with 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, 0.978

PP5

Variant 1-237791480-G-A is Pathogenic according to our data. Variant chr1-237791480-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43725.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3}. Variant chr1-237791480-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.13528G>A	p.Ala4510Thr	missense_variant	93/105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.13528G>A	p.Ala4510Thr	missense_variant	93/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 link	n.*4620G>A		non_coding_transcript_exon_variant	92/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 link	n.*4620G>A		3_prime_UTR_variant	92/104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000352

AC:

AN:

1420270

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

703410

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000255

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:

0.00000368

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000334

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 03, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 43725). This missense change has been observed in individuals with RYR2-related conditions (PMID: 15466642, 16188589, 22787013, 29453246; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4510 of the RYR2 protein (p.Ala4510Thr). -

Catecholaminergic polymorphic ventricular tachycardia

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 08, 2024	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain in the pore-forming region of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two individuals affected with a swimming-triggered arrhythmia (PMID: 15466642, 16188589) and in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 21616285). This variant is rare in the general population and has been identified in 2/198772 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2021	Variant summary: RYR2 c.13528G>A (p.Ala4510Thr) results in a non-conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 198772 control chromosomes (gnomAD), however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.13528G>A has been reported in the literature in multiple individuals affected with swimming/exercise-induced arrhythmia and with Catecholaminergic Polymorphic Ventricular Tachycardia (e.g. Choi_2004, Tester_2005, Medeiros-Domingo_2009, van der Werf_2011, van der Werf_2012, Kapplinger_2018, Giudicessi_2019, van Lint_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on data from multiple patients with the variant and through utilization of a phenotype-enhanced variant classification framework, a recent study carried out in two centers from the USA and the Netherlands, classified the variant as likely pathogenic (Giudicessi_2019). Furthermore, the variant is located in the C-terminal region which is one of the 3 identified mutation hot-spot clusters in RYR2 gene (Bauerova-Hlinkova_2020). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 26, 2023	This variant is located in 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 several individuals with suspected or confirmed catecholaminergic polymorphic ventricular tachycardia (PMID: 15466642, 19926015, 21616285, 22787013, 29453246, ClinVar SCV000285698.5). This variant has not been identified 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	May 22, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala4510Th r variant in RYR2 has been reported in at least 2 individuals, 1 individual with clinical features of CPVT (PVCs, ventricular bigeminy, couplets, syncope-exerti on, and a 440ms QTc; Tester 2005) and 1 individual with CPVT (van der Werf 2012) . In addition, this variant has also been identified in 1/16572 European chromos omes and 1/1028 Latino chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs397516510). Computational prediction tools and conservation analysis suggest that the p.Ala4510Thr variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, while there is some suspicion for a pathogenic role, the clini cal significance of the p.Ala4510Thr variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Sep 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.1

D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.024

D;.

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.93

Loss of stability (P = 0.1142);.;

MVP

0.96

MPC

1.9

ClinPred

0.96

GERP RS

4.7

Varity_R

0.33

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over