Submissions for variant NM_000540.3(RYR1):c.2122G>A (p.Asp708Asn)

gnomAD frequency: 0.00065  dbSNP: rs138874610

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000210007	SCV001816150	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-07	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 Aspartic acid with Asparagine at codon 708 of the RYR1 protein, p.(Asp708Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0007, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with congenital myopathies inherited in an autosomal recessive pattern. 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 of 0.726 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented.
Genetic Services Laboratory, University of Chicago	RCV000147418	SCV000194815	uncertain significance	not provided	2013-11-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000243154	SCV000226737	likely benign	not specified	2018-07-17	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210007	SCV000265690	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV000243154	SCV000304875	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000147418	SCV000565500	likely benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26245150, 29298851, 30155738, 23553787, 25637381, 23919265, 22473935, 21911697, 20080402, 24195946, 20839240, 32236737)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000147418	SCV000610201	uncertain significance	not provided	2017-05-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087371	SCV000659881	likely benign	RYR1-related disorder	2024-01-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000243154	SCV000711658	uncertain significance	not specified	2017-08-29	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: This variant has been reported in 6 papers in HGMD (classified as DM), with comments suggesting VUS-likely benign. This variant is classified i n ClinVar with 1 star as VUS by University of Chicago, Emory, and Biesecker lab, and is classified as Likely benign by Prevention genetics and CSER_CC_NCGL. The variant has a Max MAF of 0.10% in ExAC (69 alleles) and 0.4% in gnomAD (40 Ashk enazi alleles). Frequency too high for disease incidence. Variant is not present in emhg.org database.
Mendelics	RCV000210007	SCV001141054	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000147418	SCV002501097	uncertain significance	not provided	2021-05-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000243154	SCV002600339	likely benign	not specified	2022-10-07	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.2122G>A (p.Asp708Asn) results in a conservative amino acid change located in the first B30.2/SPRY domain (IPR001870) 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 0.00054 in 248290 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (MHS) phenotype (8.8e-05), suggesting that the variant is not causal for this phenotype. The association with recessive myopathies cannot be excluded based on this frequency, although the presence of a homozygous occurrence suggests a benign role for these phenotypes as well. The variant, c.2122G>A, has been reported in the literature in individuals affected with a variety of RYR-related myopathies (e.g. Zhou_2010, Klein_2012, Rokach_2015, Colombo_2015, Carmona_2016, Lopez_2016), however in all of these reports the presence of the variant c.6721C>T (p.Arg2241X) was noted, and multiple reports described these two variants in cis, in combination with another (likely) pathogenic missense variants in trans, which explained the recessive inheritance. A publication also reported the absence of allele specific mRNA expression in a patient derived muscle biopsy sample, likely as a result of nonsense-mediated decay caused by the p.Arg2241X stop mutation, further supporting that both variants originate from the same allele (Zhou_2010). In addition, variant co-occurrence analysis in gnomAD indicates that the c.6721C>T (p.Arg2241X) variant is likely found on the same haplotype as c.2122G>A (p.Asp708Asn) in most individuals. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 classifying as VUS (n=4), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetics and Molecular Pathology, SA Pathology	RCV000210007	SCV002761633	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing	The RYR1 c.2122G>A variant is classified as VARIANT OF UNCERTAIN SIGNIFICANCE (PM2, PP3, PS4 - supporting) The RYR1 c.2122G>A variant is a single nucleotide change from a guanine to an adenine at position 2122 which is predicted to change the amino acid aspartic acid at position 708 in the protein to asparagine. This variant is in exon 18 if 106. The variant has been previously described in patients who also carried the Arg2241* variant (PMID: 20080402; PMID: 23919265; PMID: 21911697) (PS4 – supporting). The variant is in dbSNP (rs138874610) and has been reported in population databases (gnomAD 152/279634, 1 homozygote) (PM2). There are conflicting interpretations of pathogenicity in ClinVar including Benign, Likely Benign and VUS by other diagnostic laboratories (Variation ID 159840). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Fulgent Genetics, Fulgent Genetics	RCV002483286	SCV002779178	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	2022-02-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000147418	SCV003812494	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210007	SCV004357289	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-11-09	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148798	SCV000190536	likely benign	Congenital myopathy	2014-06-01	no assertion criteria provided	research