Total submissions: 18
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000148811 | SCV001816143 | likely benign | Malignant hyperthermia, susceptibility to, 1 | 2021-03-18 | reviewed by expert panel | curation | 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). |
Eurofins Ntd Llc |
RCV000119674 | SCV000203455 | uncertain significance | not provided | 2014-03-21 | criteria provided, single submitter | clinical testing | |
Biesecker Lab/Clinical Genomics Section, |
RCV000148811 | SCV000265721 | likely benign | Malignant hyperthermia, susceptibility to, 1 | 2013-07-01 | criteria provided, single submitter | research | |
Illumina Laboratory Services, |
RCV000325643 | SCV000412390 | likely benign | Malignant hyperthermia of anesthesia | 2016-06-14 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000259113 | SCV000540243 | uncertain significance | not specified | 2017-01-24 | criteria provided, single submitter | clinical testing | 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. |
Gene |
RCV000119674 | SCV000565503 | likely benign | not provided | 2021-11-30 | criteria provided, single submitter | clinical testing | See Variant Classification Assertion Criteria. |
Ce |
RCV000119674 | SCV000575173 | uncertain significance | not provided | 2022-05-01 | criteria provided, single submitter | clinical testing | RYR1: PM2, PP3 |
Center for Pediatric Genomic Medicine, |
RCV000119674 | SCV000609897 | uncertain significance | not provided | 2017-05-12 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000530570 | SCV000660011 | likely benign | RYR1-Related Disorders | 2024-01-31 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV000119674 | SCV000852739 | uncertain significance | not provided | 2016-08-12 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000148811 | SCV001141063 | benign | Malignant hyperthermia, susceptibility to, 1 | 2023-08-22 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000148811 | SCV001440607 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Molecular Genetics, |
RCV000148811 | SCV002503639 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2022-04-14 | criteria provided, single submitter | clinical testing | 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). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/5 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PS3_Moderate, PM1, PS4_Supporting, PP1, BS1, BS2. |
Revvity Omics, |
RCV000119674 | SCV003815021 | uncertain significance | not provided | 2022-12-22 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000148811 | SCV004358113 | likely benign | Malignant hyperthermia, susceptibility to, 1 | 2022-07-13 | criteria provided, single submitter | clinical testing | |
Leiden Muscular Dystrophy |
RCV000119674 | SCV000154581 | not provided | not provided | no assertion provided | not provided | ||
CSER _CC_NCGL, |
RCV000148811 | SCV000190550 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2014-06-01 | no assertion criteria provided | research | |
Genome |
RCV001249381 | SCV001423375 | not provided | Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion | no assertion provided | phenotyping only | 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. |