rs377368967

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate

The NM_001035.3(RYR2):c.815G>A(p.Arg272His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.96

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_001035.3

PP2

Missense variant where missense usually causes diseases, RYR2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	11/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	11/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	11/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	11/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant, NMD_transcript_variant	11/104	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 28, 2023

This missense variant replaces arginine with histidine at codon 272 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 nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 07, 2017

The c.815G>A; p.Arg272His variant has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD). The arginine at position 272 is highly conserved considering 10 species (Alamut v2.9.0) and computational analyses of the effects of the p.Arg272His variant on protein structure and function indicates deleterious effects (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg272His variant with certainty. -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 05, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the RYR2 protein (p.Arg272His). 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. 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: 618352). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;T

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.80

Loss of MoRF binding (P = 0.0059);.;

MVP

0.96

MPC

1.3

ClinPred

1.0

GERP RS

6.0

Varity_R

0.64

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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