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

gnomAD frequency: 0.00001  dbSNP: rs118192168

Total submissions: 25

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
Labcorp Genetics (formerly Invitae), Labcorp	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.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV000013856	SCV005038499	likely pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2024-03-01	criteria provided, single submitter	research	PM1+PM2+PM5+PP2+PP3
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586004	SCV005038623	likely pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PM1+PM2+PM3+PM5+PP2+PP3
Ambry Genetics	RCV004658962	SCV005161788	pathogenic	Inborn genetic diseases	2024-03-29	criteria provided, single submitter	clinical testing	The c.14545G>A (p.V4849I) alteration is located in exon 101 (coding exon 101) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 14545, causing the valine (V) at amino acid position 4849 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/282784) total alleles studied. The highest observed frequency was 0.004% (1/24952) of African alleles. This variant was reported in multiple individuals with a positive IVCT test, a reported MH event, and/or a family history of a reported MH event (Carpenter, 2009; Kraeva, 2011; Brandom, 2013; Snoeck, 2015). This variant has also been shown to segregate with MHS in multiple families (Merritt, 2017). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing RYR1 function, this variant showed functionally abnormal results (Parker, 2017; Merritt, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786258	SCV005398827	pathogenic	RYR1-related myopathy	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 23919265). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as heterozygous in individuals with dominant susceptibility malignant hyperthermia and central core disease, as well as homozygous or compound heterozygous in individuals with recessive centronuclear myopathy or central core disease (PMIDs: 12136074, 25960145, 25958340, 17226826, 28818389, 19648156). This variant is classified as a diagnostic variant for malignant hyperthermia by the EMHG. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000013856	SCV000034102	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