Submissions for variant NM_000540.3(RYR1):c.3095G>A (p.Arg1032His)

gnomAD frequency: 0.00014  dbSNP: rs141942845

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580387	SCV001810070	uncertain significance	Malignant hyperthermia of anesthesia	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 arginine with histidine at codon 1032 of the RYR1 protein, p.(Arg1032His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000206, 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) (PMID:30236257 ). 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 0.547 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented.
Invitae	RCV000557798	SCV000659910	uncertain significance	RYR1-related disorder	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1032 of the RYR1 protein (p.Arg1032His). This variant is present in population databases (rs141942845, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 374974). 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. 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	RCV000721486	SCV000852559	uncertain significance	not provided	2013-10-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000721486	SCV001813361	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with neuromuscular disorders to our knowledge; This variant is associated with the following publications: (PMID: 24627108)
Athena Diagnostics	RCV000721486	SCV002771875	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481292	SCV002787377	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	2021-08-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721486	SCV003810525	uncertain significance	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000415622	SCV004358050	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1032 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 one family affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 27/266406 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.
All of Us Research Program, National Institutes of Health	RCV000415622	SCV004820797	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1032 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 one family affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 27/266406 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415622	SCV000493797	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2015-09-26	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000557798	SCV000606990	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.