ClinVar Miner

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

gnomAD frequency: 0.00107  dbSNP: rs146429605
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Total submissions: 22
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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

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