Submissions for variant NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr)

dbSNP: rs118192170

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787755	SCV000925265	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	RCV001787756	SCV000925266	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	RCV001787757	SCV000925267	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	RCV001787758	SCV000925268	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	RCV001787759	SCV000925269	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	RCV001787760	SCV000925270	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.
PharmGKB	RCV001787754	SCV000925514	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.
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000013844	SCV003930278	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-22	reviewed by expert panel	curation	The ClinGen RYR1-MHS variant curation expert panel is focused on assessing variants in RYR1 for pathogenicity as related to 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 Isoleucine with Threonine at codon 4898 of the RYR1 protein, p.(Ile4898Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in individuals with a personal or family history of an MH episode or central core disease but without sufficient information to consider the reports for informing PS4 in relation to MHS inherited in an autosomal dominant pattern (PMID: 10097181, 11709545, 12565913, 16621918 and others). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:10097181). Additional functional studies were published for this variant that did not show statistical differences in resting Ca2+ and sarcoplasmic reticulum Ca2+ content, however, those assays were not considered standard assays for variant interpretation in regard to MHS by the ClinGen RYR1 VCEP (PMID:11274444, PMID: 12642598). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS inherited in an autosomal dominant pattern. Criteria implemented: PM1_Sup, PP3_Moderate, BS3_Supporting.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000013843	SCV000611595	pathogenic	Central core myopathy	2017-10-12	criteria provided, single submitter	research
Invitae	RCV000535754	SCV000659857	pathogenic	RYR1-related disorder	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4898 of the RYR1 protein (p.Ile4898Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant central core disease (CCD) (PMID: 10097181, 11709545, 11741831, 20888934, 24561095, 25084811). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as I4897T. ClinVar contains an entry for this variant (Variation ID: 12975). 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: 10097181, 12642598, 15175001, 21825032, 22203976). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000119552	SCV000852452	pathogenic	not provided	2016-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763430	SCV000894195	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000013844	SCV000928375	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2018-09-27	criteria provided, single submitter	clinical testing	PM1, PM2, PP3, PP4, PP5
Mendelics	RCV000013844	SCV001141081	pathogenic	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000013843	SCV001429195	pathogenic	Central core myopathy	2018-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000119552	SCV001781945	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as I4898T results in altered calcium conductance, with little to no calcium release, reduced luminal calcium storage, and increased cytoplasmic calcium levels (Lynch et al., 1999); Mouse model study demonstrates I4898T results in absent voltage-induced calcium release (De Crescenzo et al., 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32528171, 32721234, 25214167, 33333461, 32140910, 20888934, 10097181, 24561095, 11709545, 11741831, 27363342, 25084811, 12161072, 22203976, 11274444, 12642598, 20461000, 20961389, 15175001, 15299003, 21825032, 16084090, 29629541, 32403337)
Revvity Omics, Revvity	RCV000119552	SCV002019927	pathogenic	not provided	2021-06-26	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004586003	SCV005077876	pathogenic	Congenital myopathy	2024-06-19	criteria provided, single submitter	curation	The heterozygous p.Ile4898Thr variant in RYR1 was identified by our study in 1 individual with congenital myopathy. The p.Ile4898Thr variant in RYR1 has been reported in at least 7 families with congenital myopathy, segregated with disease in 26 affected relatives from 2 families (PMID: 10097181, PMID: 11741831), and has been identified in 0.00008% (1/1179980) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192170). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 12975) and has been interpreted as pathogenic by multiple submitters for congenital myopathy, and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel. This variant was found to be de novo in monozygotic twins with confirmed paternity and maternity (PMID: 20888934). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. In vitro functional studies provide some evidence that the p.Ile4898Thr variant may slightly impact protein function (PMID: 10097181, 11741831). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in RYR1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital myopathy. ACMG/AMP Criteria applied: PP1_strong, PP3_moderate, PS4_moderate, PP2, PM2_supporting PS2_supporting, PS3_supporting (Richards 2015).
OMIM	RCV000013843	SCV000034090	risk factor	Central core myopathy	2001-12-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119552	SCV000154459	not provided	not provided		no assertion provided	not provided