Variant rs118192177 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_ModeratePP3_ModeratePM1PP1_ModeratePS3_Moderate

This summary comes from the ClinGen Evidence Repository: 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 threonine with arginine at codon 2206 of the RYR1 protein, p.(Thr2206Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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_Moderate (PMID:10484775, 30236257, 16244001). This variant segregates with MHS in six individuals, PP1_Moderate (PMID:10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:16163667). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score >0.85 (0.968) supports a pathogenic status for this variant, PP3_Moderate. 75e1f85c-b5bd-4e59-83c6-5d22ed39b50e75e1f85c-b5bd-4e59-83c6-5d22ed39b50eRYR1NC_000019.10g.38543551A>GNM_000540.2(RYR1):c.11798A>G|p.Tyr3933CysMONDOMONDO:0007783Likely Benign2022-01-04assertion-criteriaAutosomal dominant inheritancehttps://erepo.clinicalgenome.org/evrepo/ui/interpretation/75e1f85c-b5bd-4e59-83c6-5d22ed39b50eThis 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 tyrosine with cysteine at codon 3933 of the RYR1 protein, p.(Tyr3933Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.001332, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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) (PMID:25958340, 20681998, 23558838, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.983) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is classified as Pathogenic, (PMID:29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024620/MONDO:0007783/012

Frequency

Genomes: not found (cov: 32)

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 links:

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