rs2009813
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_001035.3(RYR2):āc.1973A>Gā(p.Asn658Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. N658N) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.1973A>G | p.Asn658Ser | missense_variant | 20/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.1973A>G | p.Asn658Ser | missense_variant | 20/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.1973A>G | p.Asn658Ser | missense_variant | 20/106 | ||||
RYR2 | ENST00000659194.3 | c.1973A>G | p.Asn658Ser | missense_variant | 20/105 | ||||
RYR2 | ENST00000609119.2 | c.1973A>G | p.Asn658Ser | missense_variant, NMD_transcript_variant | 20/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000402 AC: 10AN: 248902Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 135004
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461608Hom.: 1 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727060
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74346
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 | Dec 13, 2023 | This missense variant replaces asparagine with serine at codon 658 of the RYR2 protein. Computational prediction suggests that this variant may have a 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 catecholaminergic polymorphic ventricular tachycardia (PMID: 31155924) and in an individual suspected to be affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). It has also been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 31513939), in an individual affected with cardiomyopathy (PMID: 37477868), and in an individual affected with stillbirth (PMID: 30615648). This variant has been identified in 11/280302 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 | Jul 31, 2023 | This missense variant replaces asparagine with serine at codon 658 of the RYR2 protein. Computational prediction suggests that this variant may have a 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 catecholaminergic polymorphic ventricular tachycardia (PMID: 31155924) and in an individual suspected to be affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 29453246). It has also been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 31513939), in an individual affected with cardiomyopathy (PMID: 37477868), and in an individual affected with stillbirth (PMID: 30615648). This variant has been identified in 11/280302 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 | Apr 27, 2023 | Identified in one patient with HCM in published literature (Robyns et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 19926015, 31513939) - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 658 of the RYR2 protein (p.Asn658Ser). This variant is present in population databases (rs2009813, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 31513939; Invitae). ClinVar contains an entry for this variant (Variation ID: 201225). 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 with a positive 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. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2024 | The p.N658S variant (also known as c.1973A>G), located in coding exon 20 of the RYR2 gene, results from an A to G substitution at nucleotide position 1973. The asparagine at codon 658 is replaced by serine, an amino acid with highly similar properties. This variant has been reported in one individual from a catecholaminergic polymorphic ventricular tachycardia (CPVT) genetic testing cohort and in one individual from a hypertrophic cardiomyopathy cohort; however, clinical details were limited for both cases (Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This alteration has also been reported in a sudden death cohort (Sahlin E et al. PLoS One, 2019 Jan;14:e0210017). This amino acid position is highly 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at