Submissions for variant NM_000540.3(RYR1):c.7025A>G (p.Asn2342Ser)

gnomAD frequency: 0.00104  dbSNP: rs147213895

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148811	SCV001816143	likely benign	Malignant hyperthermia, susceptibility to, 1	2021-03-18	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 asparagine with serine at codon 2342 of the RYR1 protein p.(Asn2342Ser). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00206, which is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in over ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, at least nine of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted)( PMID:30236257, PMID:23558838, PMID:24433488, personal communication) However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been shown to segregate with IVCT status in at least three individuals across two families, PP1 (PMID:30236257, personal communication). In other families at least two genotype positive IVCT negative individuals have been reported, BS2 (PMID:15221887, personal communication). HEK293 assay shows increased sensitivity to 4CmC, PS3_Moderate (PMID: 15221887). A functional study published using B-lymphocytes showed increased acidification rates, however, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:19191333). 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 0.639 supports neither a pathogenic or a benign status. Criteria implemented include: PS3_Moderate, PM1, PP1, BS1, BS2. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386).
Eurofins Ntd Llc (ga)	RCV000119674	SCV000203455	uncertain significance	not provided	2014-03-21	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148811	SCV000265721	likely benign	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000325643	SCV000412390	likely benign	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000259113	SCV000540243	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC at a MaxMAF of 0.24% in South Asian chromosomes (including 1 homozygote). It is present in 11 papers in HGMD, most of which classify the variant as a VUS as it has been seen in affected and unaffected patients. It is classified with 1 star in ClinVar as VUS by Emory and CSER and as Likely benign by Biesecker Lab. It is not present in the www.emhg.org RYR1 database.
GeneDx	RCV000119674	SCV000565503	likely benign	not provided	2021-11-30	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
CeGaT Center for Human Genetics Tuebingen	RCV000119674	SCV000575173	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing	RYR1: PM2, PP3
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000119674	SCV000609897	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530570	SCV000660011	likely benign	RYR1-related disorder	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000148811	SCV001141063	benign	Malignant hyperthermia, susceptibility to, 1	2023-08-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000148811	SCV001440607	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000148811	SCV002503639	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace asparagine with serine at codon 2342 of the RYR1 protein, p.(Asn2342Ser). The asparagine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in exon 43 in the central region hotspot of the RYR1 cytosolic shell (amino acids 2,101-2,458). There is a small physicochemical difference between asparagine and serine. The highest population minor allele frequency in gnomAD v3.1 is 0.2% (121/68,012 alleles) in the European (non-Finnish) population. The prevalence of the variant in malignant hyperthermia (MH) susceptible individuals with positive in vitro contracture tests (IVCT) is significantly increased compared with the prevalence in the European (non-Finnish) population (the population with the maximum allele frequency) in gnomAD v3.1 (Odds ratio 3.06, 95% CI:1.64 to 5.68, p=0.0004; PMID: 19191333, 23558838, 25960145, 28224104, 30236257). There is conflicting segregation of the variant in MH susceptible and non-susceptible individuals in multiple families (PMID: 15221887, 20681998, 25960145). The variant demonstrates increased sensitivity to RYR1 agonist in an HEK293 in vitro assay with appropriate controls and in patient cells (PMID: 19191333, 31903994). The variant has been reported in at least two unrelated individuals with a negative IVCT (PMID: 15221887, 20681998). Computational evidence is uninformative for the missense substitution (REVEL = 0.639). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS3_Moderate, PM1, PS4_Supporting, PP1, BS1, BS2.
Revvity Omics, Revvity	RCV000119674	SCV003815021	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000148811	SCV004358113	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-07-13	criteria provided, single submitter	clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586560	SCV005038480	uncertain significance	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PP1_Strong+PM2+PP2+BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000259113	SCV005184505	likely benign	not specified	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.7025A>G (p.Asn2342Ser) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 1614118 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype (8.8e-05). c.7025A>G has been reported in the literature in individuals affected with malignant hyperthermia susceptibility (example: Carpenter_2009, Schiemann_2020). However, these report(s) do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. Co-occurrences with other pathogenic variants have been reported (RYR1 c.1021G>A, p.Gly341Arg; RYR1 c.7063C>T, p.Arg2355Trp), providing supporting evidence for a benign role. In functional calcium release assays, the variant showed increased sensitivity compared to wild-type control cells (Schiemann_2020). The following publications have been ascertained in the context of this evaluation (PMID: 19825159, 31903994). ClinVar contains an entry for this variant (Variation ID: 133175). Based on the evidence outlined above, the variant was classified as likely benign.
Leiden Muscular Dystrophy (RYR1)	RCV000119674	SCV000154581	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148811	SCV000190550	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV000530570	SCV000852739	uncertain significance	RYR1-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The RYR1 c.7025A>G variant is predicted to result in the amino acid substitution p.Asn2342Ser. This variant has been reported in several individuals with malignant hyperthermia (MH) (see, for example, Marchant et al. 2004. PubMed ID: 15221887; Miller et al. 2018. PubMed ID: 30236257). However, some individuals with MH who carry this variant also had another causative RYR1 variant (Carpenter et al. 2009. PubMed ID: 19825159; Supplementary File 1, Knuiman et al. 2019. PubMed ID: 30788618). In one family, this variant was detected in trans with a clear dominant, pathogenic MH variant in the proband and also observed in the proband’s three children, at least two of whom had negative in vitro contracture testing (Tammaro et al. 2011. PubMed ID: 20681998). This variant is reported in 0.21% of alleles in individuals of South Asian descent in gnomAD v2, which is much more frequent (~10 times) than the most frequent, well-characterized MH pathogenic variants. In the updated gnomAD v4, three individuals homozygous for this variant were observed. The ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel interprets this variant as likely benign in regard to autosomal dominant malignant hyperthermia susceptibility (https://www.ncbi.nlm.nih.gov/clinvar/variation/133175/). This variant has also been reported with or without a second RYR1 variant in individuals with RYR1-related myopathy (Snoeck et al. 2015. PubMed ID: 25960145; Garibaldi et al. 2019. PubMed ID: 30611313; Fusto et al. 2022. PubMed ID: 35428369). This variant was found in a parent with congenital myopathy; however, it was not found in the individual’s similarly affected daughter, and a TPM3 variant was found in both individuals (Klein et al. 2012. PubMed ID: 22473935). In summary, this variant is likely too common to be a primary cause of RYR1-related disorders and the clinical significance of this variant is uncertain due to conflicting evidence.
GenomeConnect, ClinGen	RCV001249381	SCV001423375	not provided	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 02-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.