rs397516510

Variant names:

• chr1-237791480-G-A
• rs397516510
• NM_001035.3:c.13528G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237791480-G-A
• chr1-237791480-G-C
• chr1-237791480-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PM1 PM2 PM5 PP2 PP3_Strong PP5 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5
• Conservation: PhyloP100: 10.0

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity RYR2_HUMAN there are 7 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 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, 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: {Likely_pathogenic=3, Uncertain_significance=4, Pathogenic=1}. 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 rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.13528G>A	p.Ala4510Thr	missense_variant	Exon 93 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13528G>A	p.Ala4510Thr	missense_variant	Exon 93 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*4620G>A		non_coding_transcript_exon_variant	Exon 92 of 104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*4620G>A		3_prime_UTR_variant	Exon 92 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1420270 Hom.: 0 Cov.: 27 AF XY: 0.00000284 AC XY: 2 AN XY: 703410

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.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000334 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 missense change has been observed in individuals with RYR2-related conditions (PMID: 15466642, 16188589, 22787013, 29453246; internal data). ClinVar contains an entry for this variant (Variation ID: 43725). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala4510 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 03, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1 Uncertain:1

Mar 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 06, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1 Uncertain:1

Sep 13, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Aug 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26206375, 27538377, 24025405, 16188589, 19926015, 21616285, 31112425, 15466642, 29453246, 30847666, 32152366, 17052226, 22787013) -

Cardiomyopathy Uncertain:2

May 22, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

Jun 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.89	D
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	D
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

Other links and lift over

dbSNP: rs397516510; hg19: chr1-237954780; COSMIC: COSV63693754; COSMIC: COSV63693754;