chr1-237550628-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001035.3(RYR2):c.3151C>T(p.Arg1051Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000641 in 1,590,734 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R1051H) has been classified as Likely benign.
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.3151C>T | p.Arg1051Cys | missense_variant | 27/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.3151C>T | p.Arg1051Cys | missense_variant | 27/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.3151C>T | p.Arg1051Cys | missense_variant | 27/106 | ||||
RYR2 | ENST00000659194.3 | c.3151C>T | p.Arg1051Cys | missense_variant | 27/105 | ||||
RYR2 | ENST00000609119.2 | c.3151C>T | p.Arg1051Cys | missense_variant, NMD_transcript_variant | 27/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000910 AC: 19AN: 208890Hom.: 0 AF XY: 0.000116 AC XY: 13AN XY: 112040
GnomAD4 exome AF: 0.0000674 AC: 97AN: 1438582Hom.: 2 Cov.: 30 AF XY: 0.0000968 AC XY: 69AN XY: 713134
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2020 | Has been identified independently and in association with other cardiac variants in patients with cardiomyopathy or arrhythmia (Lopez et al., 2013; Lee et al., 2015; Landstrom et al., 2017); Reported in ClinVar (ClinVar Variant ID# 201235; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25925909, 28404607, 23396983) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 14, 2019 | Variant summary: RYR2 c.3151C>T (p.Arg1051Cys) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain & B30.2/SPRY domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 205652 control chromosomes, predominantly at a frequency of 0.00064 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 25.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3151C>T has been reported in the literature in affected individuals (Hauser_2018, Landstrom_2017, Lopes_2013). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variants have been reported in our internal database (MYH7 c.2681A>G, p.Glu894Gly) and also, published (TNNI3 c.485G>A, p.R162Q) (Lopes_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 16, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely pathogenic by GeneDx. It has a Max MAF of 0.07% in ExAC (7 alleles) and 0.06% in gnomAD (16 alleles). The AA at this position is conserved. In HGMD there is another variant at this position: Arg1051Pro. In GI there are 2 other variants at this position: Arg1051Arg (likely benign) and Arg1051His (VUS4). - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 04, 2023 | This variant is located in 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 19/208890 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. - |
Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology | Apr 25, 2022 | The c.3151C>T variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS) and Indian Exome Database. The heterozygous state of the variant is present in Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD), at a low frequency. The variant is not present in our in-house exome database. The variant was previously reported in the literatures in similarly affected individuals (PMID: 23396983, 28404607, 29368431). The variant was reported to Clinvar (Accession: VCV000201235.11) with conflicting interpretations of pathogenicity (Uncertain significance/likely benign). In-silico pathogenicity prediction programs like PolyPhen-2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. Alternative variants in the same amino acid position (Arg1051His, Arg1051Pro) were previously reported in the literatures in similarly affected individuals (PMID: 27532257, 19216760) and reported to Human Genome Mutation database (HGMD IDs: CM1616928, CM090703) - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 20, 2023 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 28, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at