rs147213895
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. BS1PM1PS3_ModeratePP1BS2
This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of asparagine with serine at codon 2342 of the RYR1 protein p.(Asn2342Ser). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00206, which is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in over ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, at least nine of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted)( PMID:30236257, PMID:23558838, PMID:24433488, personal communication) However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been shown to segregate with IVCT status in at least three individuals across two families, PP1 (PMID:30236257, personal communication). In other families at least two genotype positive IVCT negative individuals have been reported, BS2 (PMID:15221887, personal communication). HEK293 assay shows increased sensitivity to 4CmC, PS3_Moderate (PMID:15221887). A functional study published using B-lymphocytes showed increased acidification rates, however, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:19191333). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score of 0.639 supports neither a pathogenic or a benign status. Criteria implemented include: PS3_Moderate, PM1, PP1, BS1, BS2. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024665/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7025A>G | p.Asn2342Ser | missense_variant, splice_region_variant | 43/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7025A>G | p.Asn2342Ser | missense_variant, splice_region_variant | 43/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7025A>G | p.Asn2342Ser | missense_variant, splice_region_variant | 43/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.479A>G | p.Asn160Ser | missense_variant, splice_region_variant, NMD_transcript_variant | 4/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7025A>G | p.Asn2342Ser | missense_variant, splice_region_variant, NMD_transcript_variant | 43/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00105 AC: 160AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00104 AC: 262AN: 251376Hom.: 0 AF XY: 0.00124 AC XY: 169AN XY: 135888
GnomAD4 exome AF: 0.00156 AC: 2278AN: 1461864Hom.: 3 Cov.: 32 AF XY: 0.00157 AC XY: 1141AN XY: 727238
GnomAD4 genome AF: 0.00105 AC: 160AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73AN XY: 74440
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 12, 2017 | - - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | RYR1: PM2, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 12, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 21, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 22, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2021 | See Variant Classification Assertion Criteria. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:3Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 13, 2022 | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 18, 2021 | This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of asparagine with serine at codon 2342 of the RYR1 protein p.(Asn2342Ser). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00206, which is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in over ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, at least nine of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted)( PMID:30236257, PMID:23558838, PMID:24433488, personal communication) However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been shown to segregate with IVCT status in at least three individuals across two families, PP1 (PMID:30236257, personal communication). In other families at least two genotype positive IVCT negative individuals have been reported, BS2 (PMID:15221887, personal communication). HEK293 assay shows increased sensitivity to 4CmC, PS3_Moderate (PMID: 15221887). A functional study published using B-lymphocytes showed increased acidification rates, however, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:19191333). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.639 supports neither a pathogenic or a benign status. Criteria implemented include: PS3_Moderate, PM1, PP1, BS1, BS2. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jul 07, 2023 | This sequence change is predicted to replace asparagine with serine at codon 2342 of the RYR1 protein, p.(Asn2342Ser). The asparagine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in exon 43 in the central region hotspot of the RYR1 cytosolic shell (amino acids 2,101-2,458). There is a small physicochemical difference between asparagine and serine. The highest population minor allele frequency in gnomAD v3.1 is 0.2% (121/68,012 alleles) in the European (non-Finnish) population. The prevalence of the variant in malignant hyperthermia (MH) susceptible individuals with positive in vitro contracture tests (IVCT) is significantly increased compared with the prevalence in the European (non-Finnish) population (the population with the maximum allele frequency) in gnomAD v3.1 (Odds ratio 3.06, 95% CI:1.64 to 5.68, p=0.0004; PMID: 19191333, 23558838, 25960145, 28224104, 30236257). There is conflicting segregation of the variant in MH susceptible and non-susceptible individuals in multiple families (PMID: 15221887, 20681998, 25960145). The variant demonstrates increased sensitivity to RYR1 agonist in an HEK293 in vitro assay with appropriate controls and in patient cells (PMID: 19191333, 31903994). The variant has been reported in at least two unrelated individuals with a negative IVCT (PMID: 15221887, 20681998). Computational evidence is uninformative for the missense substitution (REVEL = 0.639). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS3_Moderate, PM1, PS4_Supporting, PP1, BS1, BS2. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | 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 is present in ExAC at a MaxMAF of 0.24% in South Asian chromosomes (including 1 homozygote). It is present in 11 papers in HGMD, most of which classify the variant as a VUS as it has been seen in affected and unaffected patients. It is classified with 1 star in ClinVar as VUS by Emory and CSER and as Likely benign by Biesecker Lab. It is not present in the www.emhg.org RYR1 database. - |
Centronuclear myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PP1_Strong+PM2+PP2+BS2 - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Malignant hyperthermia of anesthesia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Uncertain significance and reported on 02-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at