1-237423225-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001035.3(RYR2):​c.982G>T​(p.Ala328Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A328T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RYR2
NM_001035.3 missense

Scores

1
11
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.982G>T p.Ala328Ser missense_variant Exon 12 of 105 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkc.982G>T p.Ala328Ser missense_variant Exon 12 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000609119.2 linkn.982G>T non_coding_transcript_exon_variant Exon 12 of 104 5 ENSP00000499659.2 A0A590UK06
RYR2ENST00000660292.2 linkc.982G>T p.Ala328Ser missense_variant Exon 12 of 106 ENSP00000499787.2 A0A590UKB7
RYR2ENST00000659194.3 linkc.982G>T p.Ala328Ser missense_variant Exon 12 of 105 ENSP00000499653.3 A0A590UJZ8

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Feb 24, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 328 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 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. -

Cardiomyopathy Uncertain:1
Jan 27, 2025
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 328 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function. 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 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. -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Apr 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 328 of the RYR2 protein (p.Ala328Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.49
T;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
0.17
N;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.2
N;.
REVEL
Uncertain
0.39
Sift
Benign
0.23
T;.
Polyphen
0.91
P;.
Vest4
0.54
MutPred
0.65
Gain of phosphorylation at A328 (P = 0.0349);.;
MVP
0.58
MPC
0.52
ClinPred
0.59
D
GERP RS
5.5
Varity_R
0.35
gMVP
0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-237586525; API