Total submissions: 17
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Pharm |
RCV001787761 | SCV000925285 | 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 |
RCV001787762 | SCV000925286 | 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 |
RCV001787763 | SCV000925287 | 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 |
RCV001787764 | SCV000925288 | 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 |
RCV001787765 | SCV000925387 | 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 |
RCV001787766 | SCV000925388 | 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 |
RCV001787767 | SCV000925389 | 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 |
RCV000013845 | SCV002570125 | pathogenic | Malignant hyperthermia, susceptibility to, 1 | 2022-03-29 | 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 Valine with Methionine at codon 2168 of the RYR1 protein, p.(Val2168Met). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in over 25 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 25 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:11668625; PMID:30236257; PMID:20681998 and others). Functional studies in human myotubes from nine individuals (5 families) showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:15299003). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS eight individuals PP1_Strong (PMID:12434264, PMID:11575529). A REVEL score >0.85 (0.896)supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. |
Invitae | RCV000557804 | SCV000659996 | pathogenic | RYR1-related disorder | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2168 of the RYR1 protein (p.Val2168Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 9497245, 11668625, 19648156, 25466363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12976). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 11668625). For these reasons, this variant has been classified as Pathogenic. |
Institute of Human Genetics Munich, |
RCV000578323 | SCV000680358 | pathogenic | Congenital multicore myopathy with external ophthalmoplegia | 2017-11-15 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV000119656 | SCV000852713 | pathogenic | not provided | 2017-09-27 | criteria provided, single submitter | clinical testing | |
Laboratory of Medical Genetics, |
RCV001729347 | SCV001976854 | pathogenic | Central core myopathy | 2021-10-01 | criteria provided, single submitter | clinical testing | PM2, PP2, PP3, PP5 |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003398498 | SCV004122468 | pathogenic | Malignant hyperthermia of anesthesia | 2023-10-04 | criteria provided, single submitter | clinical testing | Variant summary: RYR1 c.6502G>A (p.Val2168Met) results in a conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250298 control chromosomes. c.6502G>A has been reported in the literature in multiple individuals affected with autosomal dominant Malignant Hyperthermia Susceptibility with evidence of familial co-segregation (e.g. Manning_1998, Girard_2001). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing altered calcium-induced calcium release in vitro, however, without evidence to confirm variant effect in skeletal muscle (e.g. Murayama_2016). The following publications have been ascertained in the context of this evaluation (PMID: 11673462, 9497245, 27586648). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Laboratory for Molecular Medicine, |
RCV003398498 | SCV004848341 | pathogenic | Malignant hyperthermia of anesthesia | 2020-06-11 | criteria provided, single submitter | clinical testing | The p.Val2168Met variant in RYR1 has been previously reported in >25 individuals with malignant hyperthermia susceptibility (MHS), segregated in >10 affected family members, and was absent from large population studies (PMID, 19648156, 25466363, 11668625, 9497245, 30236257, 8010475, 29635721). In vitro functional studies showed that this variant results in an increased sensitivity to caffeine, as well as additional findings that indicate that this variant would result in a MHS phenotype (27586648, 12732639). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia susceptibility. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3, PS3_Supporting. |
OMIM | RCV000013845 | SCV000034092 | risk factor | Malignant hyperthermia, susceptibility to, 1 | 2001-10-15 | no assertion criteria provided | literature only | |
Leiden Muscular Dystrophy |
RCV000119656 | SCV000154563 | not provided | not provided | no assertion provided | not provided | ||
OMIM | RCV001729347 | SCV005046821 | pathogenic | Central core myopathy | 2001-10-15 | no assertion criteria provided | literature only |