Submissions for variant NM_000540.3(RYR1):c.6478G>A (p.Gly2160Ser)

gnomAD frequency: 0.00025  dbSNP: rs143398211

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001124361	SCV001816185	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-06	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 Glycine with Serine at codon 2160 of the RYR1 protein, p.(Gly2160Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0006, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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), PS4_Supporting (PMID:30236257). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. 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 0.635 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.
GeneDx	RCV000438220	SCV000521245	uncertain significance	not provided	2024-06-23	criteria provided, single submitter	clinical testing	Observed with another missense variant in the RYR1 gene in an African American patient with exertional rhabdomyolysis and malignant hyperthermia susceptibility, however, familial segregation information was not provided (PMID: 19807743); Identified in a patient with malignant hyperthermia susceptibility, however the G2160S variant did not segregate with disease in the family as other affected family members were heterozygous for a different variant in the RYR1 gene (PMID: 28403410); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 23476141, 25637381, 28403410, 12668474, 33767344, 19807743)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036862	SCV001200248	likely benign	RYR1-related disorder	2023-12-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001124361	SCV001283308	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001124362	SCV001283309	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000438220	SCV002541518	uncertain significance	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478417	SCV002799536	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	2022-04-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001124361	SCV004820882	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 2160 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one family affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 24/281882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington	RCV000148821	SCV000190560	uncertain significance	Malignant hyperthermia and exertional rhabdomyolosis	2014-06-01	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV001036862	SCV000607034	not provided	RYR1-related disorder		no assertion provided	phenotyping only	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.