1-237369546-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001035.3(RYR2):c.322G>A(p.Gly108Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 1,562,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
RYR2
NM_001035.3 missense
NM_001035.3 missense
Scores
6
9
3
Clinical Significance
Conservation
PhyloP100: 6.75
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 Likely_benign. Variant got -3 ACMG points.
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.
BS2
High AC in GnomAdExome4 at 18 AD gene.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR2 | ENST00000366574.7 | c.322G>A | p.Gly108Ser | missense_variant | 6/105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
| RYR2 | ENST00000609119.2 | n.322G>A | non_coding_transcript_exon_variant | 6/104 | 5 | ENSP00000499659.2 | ||||
| RYR2 | ENST00000660292.2 | c.322G>A | p.Gly108Ser | missense_variant | 6/106 | ENSP00000499787.2 | ||||
| RYR2 | ENST00000659194.3 | c.322G>A | p.Gly108Ser | missense_variant | 6/105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000227 AC: 4AN: 176116Hom.: 0 AF XY: 0.0000108 AC XY: 1AN XY: 92838
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GnomAD4 exome AF: 0.0000128 AC: 18AN: 1410732Hom.: 0 Cov.: 30 AF XY: 0.0000129 AC XY: 9AN XY: 696594
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GnomAD4 genome 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 18, 2024 | Variant summary: RYR2 c.322G>A (p.Gly108Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 176116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322G>A has been reported in the literature in at-least one individual affected withdilated cardiomyopathy, however this individual also had a co-occurrence in TTN gene (c.81341dup) (Kolokotronis_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32659924). ClinVar contains an entry for this variant (Variation ID: 463594). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces glycine with serine at codon 108 of 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 an individual affected with dilated cardiomyopathy and arrhythmia, who also carried a truncating variant in the TTN gene (PMID: 32659924). This variant has been identified in 4/176116 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 | Aug 09, 2023 | This missense variant replaces glycine with serine at codon 108 of 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 an individual affected with dilated cardiomyopathy and arrhythmia, who also carried a truncating variant in the TTN gene (PMID: 32659924). This variant has been identified in 4/176116 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 | Dec 10, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar Variant ID#463594; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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) - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 28, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 108 of the RYR2 protein (p.Gly108Ser). 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 variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 463594). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2023 | The p.G108S variant (also known as c.322G>A), located in coding exon 6 of the RYR2 gene, results from a G to A substitution at nucleotide position 322. The glycine at codon 108 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Benign
T;.
Polyphen
D;.
Vest4
MutPred
Loss of helix (P = 0.0196);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at