chr19-38566986-G-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
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 Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024057/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00332 AC: 505AN: 152106Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00337 AC: 696AN: 206260Hom.: 2 AF XY: 0.00361 AC XY: 400AN XY: 110706
GnomAD4 exome AF: 0.00556 AC: 8003AN: 1438904Hom.: 23 Cov.: 32 AF XY: 0.00547 AC XY: 3901AN XY: 713364
GnomAD4 genome AF: 0.00332 AC: 505AN: 152224Hom.: 0 Cov.: 31 AF XY: 0.00321 AC XY: 239AN XY: 74424
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:6
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 22, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 12, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2020 | This variant is associated with the following publications: (PMID: 18813041, 23476141, 27147545, 23394784, 22473935, 24195946, 23329375, 25735680, 21918424, 27153395, 26332594, 27058611, 27663056, 28326467, 26019235, 30842289, 32381029) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | RYR1: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Malignant hyperthermia, susceptibility to, 1 Benign:5
Benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
Benign, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 17, 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 Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 01, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | - - |
Malignant hyperthermia of anesthesia Benign:2Other:1
Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 01, 2023 | Variant summary: RYR1 c.13513G>C (p.Asp4505His) results in a non-conservative amino acid change located in the ryanodine receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 206460 control chromosomes, including 2 homozygotes, and predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype determined by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (0.0054 vs 0.0038; Johnston_2021), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.13513G>C has been reported in the literature in individuals affected with malignant hyperthermia susceptibility, King-Denborough syndrome, congenital myopathy, RYR1-related late-onset axial myopathy, core myopathy, idiopathic hyperCKemia and atrioventricular septal defect; however no strong evidences of pathogenicity were found in these studies (e.g. Malandrini_2008, Groom_2011, Klein_2012, Maggi_2013, Loseth_2013, Klingler_2014, Gillies_2015, Priest_2016, Jokela_2019, Elliott_2022, Fusto_2022). Thus, these reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility or other RYR2-related disorders. This variant was found to cause a modest increase in caffeine sensitivity as compared to the wild type protein, and to further enhance such sensitivity when present in cis or trans with another variant, p.R3983C (Groom_2011). Twelve submitters, including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2)/likely benign (n=6) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 07, 2020 | - - |
RYR1-related disorder Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 16, 2021 | 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). - |
Congenital hip dislocation;C0699743:Congenital muscular dystrophy;C0746674:Generalized muscle weakness;C4021726:EMG: myopathic abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 14, 2014 | - - |
Myopathy, progressive axial with cataracts Benign:1
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 06, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at