Submissions for variant NM_000540.3(RYR1):c.4711A>G (p.Ile1571Val)

gnomAD frequency: 0.00107  dbSNP: rs146429605

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148793	SCV001816160	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 Isoleucine with Valine at codon 1571 of the RYR1 protein, p.(Ile1571Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0014, 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 five 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, PMID:20681998, PMID:25658027, PMID: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 of 0.56 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1.
Genetic Services Laboratory, University of Chicago	RCV000147429	SCV000194836	uncertain significance	not provided	2014-04-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000147429	SCV000331484	uncertain significance	not provided	2018-02-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000375527	SCV000540246	uncertain significance	not specified	2016-04-25	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: 2 papers describe as LB; ExAC: 0.5% (3/608) Latino chromosomes; ClinVar: 1 LB, 1 VUS; ML: Frequent for disease. 0.2% Eur
CeGaT Center for Human Genetics Tuebingen	RCV000147429	SCV000575167	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	RYR1: PM3:Strong, PM2, PP3, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655534	SCV000777465	uncertain significance	RYR1-related disorder	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1571 of the RYR1 protein (p.Ile1571Val). This variant is present in population databases (rs146429605, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Ile1571Val), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 22473935, 20681998, 28259615, 30611313). ClinVar contains an entry for this variant (Variation ID: 159851). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000147429	SCV000852638	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765446	SCV000896737	uncertain significance	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
Mendelics	RCV000148793	SCV001141060	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000147429	SCV001715271	uncertain significance	not provided	2020-02-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000147429	SCV001751706	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30611313, 28259615, 28269792, 20681998, 25214167, 25958340, 23919265, 25735680, 24950660, 25960145, 25637381, 24055113, 22473935, 26332594, 31517061)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729407	SCV001976676	likely pathogenic	Central core myopathy	2021-10-01	criteria provided, single submitter	clinical testing	PM1, PM2, PM3, PP2, PP4, PP5
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252003	SCV002523748	uncertain significance	See cases	2020-07-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM3
MGZ Medical Genetics Center	RCV000148793	SCV002580954	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2022-07-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000147429	SCV003827508	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000375527	SCV004122729	uncertain significance	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.4711A>G (p.Ile1571Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 167524 control chromosomes (gnomAD). c.4711A>G has been reported in the literature in cis with c.10097G>A and c.11798A>G in individuals affected with RYR1-Associated Myopathy (malignant hyperthermia (MH), congenital myopathy, central core disease (CCD), and multi minicore disease (MmD) (examples: Rocha_2014, Savarese_2014, Fiszer_2015, Snoeck_2015, Gillies_2015, Kraeva_2015, Garibaldi_2019, Granger_ 2023). It is unclear if one of the three variants or the combined effect of these mutations are causative for the RYR1-associated diseases in reported individuals. The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 25658027, 25960145, 24950660, 25214167, 25735680, 25958340, 36628841). Fourteen submitters (including ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9), benign/likely benign (n=4) and likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000148793	SCV004358073	likely benign	Malignant hyperthermia, susceptibility to, 1	2023-03-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993827	SCV004812469	uncertain significance	Anterior segment dysgenesis 7	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace isoleucine with valine at codon 1571, p.(Ile1571Val). The isoleucine residue is moderately conserved (100 vertebrates, UCSC), and is located in exon 33. There is a small physicochemical difference between isoleucine and valine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.14% (114/83,130 alleles) in the European (non-Finnish) population. This variant is almost always reported in a haplotype with two other RYR1 missense variants, p.[(Ile1571Val);(Arg3366His);(Tyr3933Cys)]. The haplotype has been detected in at least 19 individuals with a phenotype consistent with RYR1-related myopathy with/without malignant hyperthermia susceptibility (MHS). Of those individuals, 14 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 8 of those were confirmed in trans by parental/family testing (PMID: 22473935, 23394784, 24950660, 25958340, 25960145, 30611313, 32236737, 35428369). The haplotype segregates with myopathy in a recessive mode of inheritance in at least one family, and there is conflicting evidence for segregation with MHS (PMID: 22473935, 23394784, 25958340). There is limited evidence that the monoallelic haplotype is associated with RYR1-related disease, it has been detected in individuals that unaffected, with MHS, and symptomatic hyperCKaemia (PMID: 25958340, 28259615, 31517061, 32236737). The variant has been detected alone in at least 2 individuals with muscle-related phenotypes, one was compound heterozygous with a pathogenic variant (PMID: 29701772, 35428369). Multiple lines of computational evidence have conflicting predictions for the missense substitution (2/5 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3_Supporting. The haplotype is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1.
Breakthrough Genomics, Breakthrough Genomics	RCV000147429	SCV005207129	likely benign	not provided		criteria provided, single submitter	not provided
CSER _CC_NCGL, University of Washington	RCV000148793	SCV000190531	likely benign	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001729407	SCV004041717	uncertain significance	Central core myopathy	2023-10-09	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV000655534	SCV005368688	uncertain significance	RYR1-related disorder	2023-02-28	no assertion criteria provided	clinical testing