rs564806219
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001035.3(RYR2):āc.5294C>Gā(p.Ser1765Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1765F) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.5294C>G | p.Ser1765Cys | missense_variant | 37/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.5294C>G | p.Ser1765Cys | missense_variant | 37/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.5294C>G | p.Ser1765Cys | missense_variant | 37/106 | ||||
RYR2 | ENST00000659194.3 | c.5294C>G | p.Ser1765Cys | missense_variant | 37/105 | ||||
RYR2 | ENST00000609119.2 | c.5294C>G | p.Ser1765Cys | missense_variant, NMD_transcript_variant | 37/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000181 AC: 45AN: 248986Hom.: 0 AF XY: 0.000215 AC XY: 29AN XY: 135060
GnomAD4 exome AF: 0.000105 AC: 154AN: 1461710Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81AN XY: 727138
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 29, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2020 | Reported in association with HCM and sudden unexplained cardiac arrest/death (Brion et al., 2014; Lopes et al., 2015; Jimenez-Jaimez et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Is 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: 28404607, 26899768, 25351510, 24981977, 26189708) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 08, 2017 | The p.Ser1765Cys variant (rs564806219) has been observed in an individual included in a cohort of hypertrophic cardiomyopathy patients (Lopes 2015), an individual with a suspected diagnosis of catecholaminergic polymorphic ventricular tachycardia who did not meet full diagnostic criteria (Jimenez-Jaimez 2015), and in a case of sudden unexplained death (Brion 2014). However, so co-segregation data is available for this variant, and it is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.017% (identified in 48 out of 276,878 chromosomes). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 404210). The serine at codon 1765 is highly conserved considering 10 species up to chicken (Alamut software v2.9), although computational analyses return mixed results regarding the effect of this variant on RYR2 protein structure/function (SIFT: damaging, PolyPhen2: benign, and Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Ser1765Cys variant cannot be determined with certainty. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes | Jun 01, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Feb 02, 2017 | - - |
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 09, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 28, 2021 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 26, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 26, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2023 | The p.S1765C variant (also known as c.5294C>G), located in coding exon 37 of the RYR2 gene, results from a C to G substitution at nucleotide position 5294. The serine at codon 1765 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was reported in a case of sudden cardiac death (Brion M et al. Electrophoresis, 2014 Nov;35:3111-6), and in an individual with unexplained cardiac arrest who did not meet the diagnostic criteria of catecholaminergic polymorphic ventricular tachycardia (Jiménez-Jáimez J et al. Am. J. Cardiol., 2015 Sep;116:894-9). In addition, this alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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. - |
RYR2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 20, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at