Submissions for variant NM_000540.3(RYR1):c.6838G>A (p.Val2280Ile)

gnomAD frequency: 0.00002  dbSNP: rs193922797

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000185536	SCV001810122	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-05-20	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 isoleucine at codon 2280 of the RYR1 protein, p.(Val2280Ile). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000035, a frequency consistent with pathogenicity for MHS. This variant has been reported in three 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:30864471, PMID:30236257; MHIU Toronto - MH proband CGS 45). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:36208971). 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 of 0.641 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1.
Genetic Services Laboratory, University of Chicago	RCV000502398	SCV000596904	uncertain significance	not specified	2017-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691232	SCV000818981	pathogenic	RYR1-related disorder	2023-12-28	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 2280 of the RYR1 protein (p.Val2280Ile). This variant is present in population databases (rs193922797, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions and/or malignant hyperthermia susceptibility (PMID: 12208234, 30236257, 30788618, 31559918, 36208971; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133172). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 36208971). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000119670	SCV000852733	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000185536	SCV001440604	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000119670	SCV002770435	uncertain significance	not provided	2021-09-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492409	SCV002786864	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-10-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119670	SCV003812488	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323407	SCV004028792	likely pathogenic	Malignant hyperthermia of anesthesia	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6838G>A (p.Val2280Ile) 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 allele was found at a frequency of 2.4e-05 in 250004 control chromosomes. c.6838G>A has been reported in the literature in multiple individuals affected with Malignant Hyperthermia Susceptibility supported by a diagnostic in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (example, Galli_2002, Scalco_2016, Oberg_2016, Knulman_2019, Hudig_2019, Sadhasivam_2019, White_2022). Of these, in one report of families with this variant, eight transmissions of the variant allele and 2 transmissions of the reference allele to affected Malignant Hyperthermia Susceptible individuals was reported (White_2022). This study included this variant among RYR-1 disease causing variants for diagnostic use managed by the European Malignant Hyperthermia Group. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, demonstrating hypersensitivity to an RyR1 agonist in calcium release assays (White_2022). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters to include the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, reported the variant with conflicting assessments (VUS, n=6; LP, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000185536	SCV004358111	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2280 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in at least 4 families or individuals affected with malignant hyperthermia susceptibility (PMID: 16835904, 30236257, 30864471, 36208971, 36208971, ClinVar: SCV001810122.1). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 individuals of 1 family (PMID: 36208971). This variant has been identified in 6/250004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV000119670	SCV005078063	uncertain significance	not provided	2024-02-16	criteria provided, single submitter	clinical testing	Reported in one family affected with malignant hyperthermia; however, familial segregation information was not provided (PMID: 30236257); Reported in two unrelated individuals and multiple affected individuals within one family with malignant hyperthermia susceptibility; however, this variant did not segregate with all affected individuals in this family (PMID: 36208971, 12208234, 30864471); Reported in two unrelated individuals with rhabdomyolysis; one individual was also affected with muscle cramps and elevated CK levels (PMID: 27431030, 30788618); Reported in a patient with muscle weakness and cramps, chronically elevated CK, heat intolerance, and an episode of hyperthermia and leg stiffness who inherited the variant from their mother with a history of multiple uncomplicated general anesthetics (PMID: 31559918); Published functional studies suggest this variant leads to hypersensitivity of the RYR1 channel (PMID: 36208971); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16835904, 16115682, 12208234, 27431030, 20301325, 12668474, 33767344, 36208971, 31559918, 30864471, 28007021, 30788618, 30236257)
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000119670	SCV005198092	likely pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (RYR1)	RCV000119670	SCV000154577	not provided	not provided		no assertion provided	not provided
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185536	SCV000238413	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2014-07-17	no assertion criteria provided	research	This test identified one heterozygous variant (c.6838G>A;p.Val2280Ile) in the RYR1 gene (see Table IIIA). Variants in this gene have been associated with increased risk of malignant hyperthermia (autosomal dominant) and different types of congenital myopathies - central core disease (autosomal dominant or autosomal recessive), multiminicore disease (autosomal recessive), congenital fiber type disproportion (autosomal dominant or autosomal recessive). The RYR1 gene encodes for calcium channels that play a critical role in the movement of skeletal muscles. Risk for malignant hyperthermia is predominantly associated with the use of general anesthesia with specific anesthetics, which can trigger an episode (hypermetabolism, rhabdomyolysis, hyperkalaemia, cardiac arrhythmia). A very small number of individuals with malignant hyperthermia susceptibility appear to be at risk for heat stroke or exercise-induced rhabdomyolysis,). Malignant hyperthermia has been reported to occur in individuals without anesthetic exposure. If an episode is untreated, it can be life threatening. Alternative anesthetic treatments are available for known individuals susceptible to malignant hyperthermia. This variant has been reported in a family susceptible to malignant hyperthermia based on biochemical testing (Galli et al 2002,PMID: 12208234; Galli et al. 2006, PMID: 16835904), and computational evidence is also suggestive of this variant being a pathogenic variant.