Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Pharm |
RCV001788021 | SCV000925498 | drug response | desflurane response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Pharm |
RCV001788022 | SCV000925540 | drug response | enflurane response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Pharm |
RCV001788023 | SCV000925541 | drug response | halothane response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Pharm |
RCV001788024 | SCV000925542 | drug response | isoflurane response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Pharm |
RCV001788025 | SCV000925543 | drug response | methoxyflurane response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Pharm |
RCV001788026 | SCV000925544 | drug response | sevoflurane response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Pharm |
RCV001788027 | SCV000925545 | drug response | succinylcholine response - Toxicity | 2021-03-24 | reviewed by expert panel | curation | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. |
Clin |
RCV001588961 | SCV001816171 | likely pathogenic | Malignant hyperthermia, susceptibility to, 1 | 2023-04-07 | 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 Arginine with Histidine at codon 2508 of the RYR1 protein, p.(Arg2508His). This variant is not present in the six major gnomAD populations at the time this variant was interpreted. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, six of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:23460944, PMID:25960145). This variant was determined to be de novo without confirmed parentage in one individual, PS2/PM6_Supporting (PMID:17483490). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26381711, PMID:27586648). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.898) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS2/PM6_Supporting, PS3_Moderate, PS4, PP3_Moderate. |
Labcorp Genetics |
RCV000528193 | SCV000660028 | pathogenic | RYR1-related disorder | 2025-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2508 of the RYR1 protein (p.Arg2508His). This variant is present in population databases (rs193922818, gnomAD 0.01%). This missense change has been observed in individual(s) with central core myopathy, King Denborough syndrome, malignant hyperthermia, and/or muscle weakness (PMID: 16621918, 16732084, 16835904, 17483490, 20142353, 21282829, 23558838, 25960145). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 133207). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 26381711). This variant disrupts the p.Arg2508 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16621918, 19685112, 26381711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Prevention |
RCV000119719 | SCV000852781 | pathogenic | not provided | 2017-10-20 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000119719 | SCV001446515 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000119719 | SCV002019972 | pathogenic | not provided | 2019-02-28 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000119719 | SCV003933429 | pathogenic | not provided | 2024-11-18 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect on calcium homeostasis (PMID: 26381711); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34850017, 21282829, 16917943, 16835904, 25960145, 23558838, 27586648, 30236257, 31127727, 32528171, 32381727, 16732084, 35428369, 38002952, 38188551, 16621918, 26381711, 17483490) |
RYR1 database | RCV000119719 | SCV000154626 | not provided | not provided | no assertion provided | not provided |