Submissions for variant NM_000540.3(RYR1):c.9262G>A (p.Val3088Met)

gnomAD frequency: 0.00046  dbSNP: rs145044872

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000721734	SCV000234981	likely benign	not provided	2021-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26994242, 28326467)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203140	SCV000257716	uncertain significance	Malignant hypothermia	2015-07-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000326085	SCV000412636	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000383042	SCV000412637	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000272384	SCV000412638	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000329734	SCV000412639	likely benign	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084220	SCV000660084	likely benign	RYR1-related disorder	2024-01-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000721734	SCV000705502	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000721734	SCV001249996	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR1: PP3, BS2
Molecular Genetics, Royal Melbourne Hospital	RCV002225092	SCV002503664	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace valine with methionine at codon 3088 of the RYR1 protein, p.(Val3088Met). The valine residue is highly conserved (100 vertebrates, UCSC), and is not present in a known functional domain. There is a small physicochemical difference between valine and methionine. The variant is present in a large population cohort at a frequency of 0.05% (rs145044872, 152/282,802 alleles, 1 homozygote in gnomAD v2.1.1). It has been identified in the homozygous state in a control age 70-75 (gnomAD v2.1.1), a patient with recessive congenital core myopathy (PMID: 26994242), and a case with multiple anatomical abnormalities (Mygene2.org), and compound heterozygous with a RYR1 VUS (p.Val4547Met) in a malformed foetus with pulmonary hypoplasia (CGC genetics, Portugal). Additionally, it has been identified heterozygous in a case with exertional heat stroke and a positive in vitro muscle contracture test (PMID: 26994242), a case with exercise induced rhabdomyolysis (UCL Institute of Neurology, London), and as an incidental finding in an individual with advanced terminal cancer (PMID: 28003660). The variant is not present on the European Malignant Hyperthermia Group database and has previously been reported as likely benign (ClinVar ID: 201158). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Dept of Medical Biology, Uskudar University	RCV003318366	SCV004022002	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP3, BS1
Color Diagnostics, LLC DBA Color Health	RCV002225092	SCV004358165	likely benign	Malignant hyperthermia, susceptibility to, 1	2023-01-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001084220	SCV000852863	uncertain significance	RYR1-related disorder	2023-11-20	no assertion criteria provided	clinical testing	The RYR1 c.9262G>A variant is predicted to result in the amino acid substitution p.Val3088Met. This variant was reported in a patient with exertional heat stroke who was also positive for an in vitro muscle contraction test. In addition, it was mentioned in the same report that the p.Val3088Met variant was previously identified in the same laboratory in the homozygous state in a patient with recessive congenital core myopathy (Roux-Buisson et al. 2016. PubMed ID: 26994242). We have detected this variant at PreventionGenetics previously in one Malignant Hyperthermia (MH) patient. This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.