rs780484631
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_001035.3(RYR2):c.9673G>A(p.Gly3225Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,624 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3225V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.9673G>A | p.Gly3225Ser | missense_variant | 68/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.9673G>A | p.Gly3225Ser | missense_variant | 68/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.9673G>A | p.Gly3225Ser | missense_variant | 68/106 | ||||
RYR2 | ENST00000659194.3 | c.9673G>A | p.Gly3225Ser | missense_variant | 68/105 | ||||
RYR2 | ENST00000609119.2 | c.*708G>A | 3_prime_UTR_variant, NMD_transcript_variant | 66/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249094Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135126
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461624Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727098
GnomAD4 genome ? Cov.: 32
ClinVar
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 | Nov 30, 2023 | This missense variant replaces glycine with serine at codon 3225 of 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 been reported in two individuals affected with unexplained sudden cardiac death (PMID: 29181379, 27332903). This variant has been identified in 4/249094 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 | Oct 01, 2023 | This missense variant replaces glycine with serine at codon 3225 of 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 been reported in two individuals affected with unexplained sudden cardiac death (PMID: 29181379, 27332903). This variant has been identified in 4/249094 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 | Mar 29, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3225 of the RYR2 protein (p.Gly3225Ser). This variant is present in population databases (rs780484631, gnomAD 0.006%). This missense change has been observed in individual(s) with unexplained sudden cardiac death (PMID: 27332903). ClinVar contains an entry for this variant (Variation ID: 519478). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2017 | The p.G3225S variant (also known as c.9673G>A), located in coding exon 68 of the RYR2 gene, results from a G to A substitution at nucleotide position 9673. The glycine at codon 3225 is replaced by serine, an amino acid with similar properties. This alteration was seen in one individual from a sudden cardiac death cohort, who also carried a missense alteration in MYBPC3 (Bagnall RD et al. N. Engl. J. Med., 2016 Jun;374:2441-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at