rs762899950

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

The NM_001035.3(RYR2):c.3827C>T(p.Thr1276Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,553,108 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.90

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 2 ACMG points.

PP2

Missense variant where missense usually causes diseases, RYR2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.3827C>T	p.Thr1276Ile	missense_variant	31/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.3827C>T	p.Thr1276Ile	missense_variant	31/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.3827C>T	p.Thr1276Ile	missense_variant	31/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.3827C>T	p.Thr1276Ile	missense_variant	31/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.3827C>T	p.Thr1276Ile	missense_variant, NMD_transcript_variant	31/104	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000982

AC:

AN:

203696

Hom.:

AF XY:

0.00000926

AC XY:

AN XY:

108024

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000210

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1400964

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

689714

show subpopulations

Gnomad4 AFR exome

AF:

0.0000314

Gnomad4 AMR exome

AF:

0.00

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:

0.0000139

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

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

Dec 18, 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/235098 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 30, 2023

This missense variant replaces threonine with isoleucine at codon 1276 of the RYR2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 3/235098 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2022

Has not been previously published as pathogenic or benign to our knowledge; Not 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); 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: 19926015) -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1276 of the RYR2 protein (p.Thr1276Ile). This variant is present in population databases (rs762899950, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 238231). 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. 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. -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.29

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Pathogenic

0.69

Sift

Benign

0.045

D;.

Polyphen

0.020

B;.

Vest4

0.94

MutPred

0.50

Loss of relative solvent accessibility (P = 0.0404);.;

MVP

0.97

MPC

0.41

ClinPred

0.97

GERP RS

5.0

Varity_R

0.50

gMVP

0.75

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

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