ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14545G>A (p.Val4849Ile)

gnomAD frequency: 0.00001  dbSNP: rs118192168
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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787789 SCV000925466 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.
PharmGKB RCV001787790 SCV000925507 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.
PharmGKB RCV001787791 SCV000925508 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.
PharmGKB RCV001787792 SCV000925509 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.
PharmGKB RCV001787793 SCV000925510 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.
PharmGKB RCV001787794 SCV000925511 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.
PharmGKB RCV001787795 SCV000925512 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.
GeneDx RCV000119527 SCV000566861 pathogenic not provided 2022-04-25 criteria provided, single submitter clinical testing Observed as a single variant in several families with a history of both malignant hyperthermia and CCD, as well as in an individual with scapular winging, limb weakness and a muscle biopsy with increased internal nuclei (Carpenter et al., 2009; Loseth et al., 2013).; Observed in the heterozygous state in multiple families with malignant hyperthermia, confirmed by in vitro contracture testing (IVCT) (Miller et al., 2018); Functional studies showed that V4849I increases both receptor sensitivity to caffeine and resulting calcium release (Merritt et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16372898, 32978841, 30788618, 31447099, 12136074, 17483490, 18253926, 23558838, 23329375, 22473935, 19648156, 17226826, 25958340, 16917943, 28818389, 29635721, 32381029, 30932294, 30291343, 28403410, 28527222, 30236257, 32665702, 32528171, 20681998)
PreventionGenetics, part of Exact Sciences RCV000119527 SCV000852429 pathogenic not provided 2016-06-08 criteria provided, single submitter clinical testing
Mendelics RCV000990211 SCV001141080 pathogenic Malignant hyperthermia, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001060435 SCV001225122 pathogenic RYR1-related disorder 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4849 of the RYR1 protein (p.Val4849Ile). This variant is present in population databases (rs118192168, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 12136074, 22473935, 28818389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 19648156). ClinVar contains an entry for this variant (Variation ID: 12984). 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) has been performed at Invitae 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. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000119527 SCV002019961 pathogenic not provided 2023-03-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000119527 SCV002498471 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000990211 SCV002580953 pathogenic Malignant hyperthermia, susceptibility to, 1 2022-07-27 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000990211 SCV002761450 pathogenic Malignant hyperthermia, susceptibility to, 1 2021-10-20 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001060435 SCV004013276 pathogenic RYR1-related disorder 2023-06-06 criteria provided, single submitter clinical testing PS3, PM1, PM2, PP3, PP1
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000990211 SCV004183381 pathogenic Malignant hyperthermia, susceptibility to, 1 2020-07-11 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM2, PM3
Color Diagnostics, LLC DBA Color Health RCV000990211 SCV004358229 pathogenic Malignant hyperthermia, susceptibility to, 1 2023-03-29 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 4849 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in HEK293 cells have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 28403410). This variant has been reported in over 15 individuals affected with malignant hyperthermia episodes and in more than 10 families affected with malignant hyperthermia susceptibility (PMID: 15731587, 19346234, 19648156, 23558838, 24433488, 25960145, 28403410, 28527222, 30788618). It has been shown that this variant segregates with disease in at least 3 families (PMID: 28403410). This variant has been identified in 5/282784 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017242 SCV004848370 pathogenic Malignant hyperthermia of anesthesia 2020-06-11 criteria provided, single submitter clinical testing The p.Val4849Ile variant in RYR1 has been reported in >15 individuals with malignant hyperthermia, and segregated in >15 affected family members (Brandom 2013, Broman 2009, Snoeck 2015, Klinger 2014, Carpenter 2009). It has also been reported in 3 individuals with recurrent rhabdomyolysis or myalgia with hyperCKemia and two individuals with late onset axial myopathy (Witting 2018, Loseth 2013, Snoeck 2015). Furthermore, this variant has been reported in the compound heterozygous state in 5 individuals with congenital myopathy, central core disease, or centronuclear myopathy (Ducreux 2006, Kraeva 2015, Abath Neto 2017, Kossugue 2007, Monnier 2008, Zhou 2007). In vitro functional studies support that this variant results in increased sensitivity to RYR1-agonists (Merrit 2017, Parker 2017, Ducreux 2006). It has been identified in 5/282784 of the total chromosomes in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for both autosomal dominant malignant hyperthermia and autosomal recessive congenital myopathy / central core disease. ACMG/AMP criteria applied: PS4, PM3_Strong, PP1_Strong, PM2, PP3, PS3_Supporting.
OMIM RCV000013855 SCV000034102 pathogenic Central core disease, autosomal recessive 2008-05-01 no assertion criteria provided literature only
OMIM RCV000013856 SCV000034103 pathogenic Congenital multicore myopathy with external ophthalmoplegia 2008-05-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (RYR1) RCV000119527 SCV000154434 not provided not provided no assertion provided not provided

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