Submissions for variant NM_000540.3(RYR1):c.9758T>C (p.Ile3253Thr)

gnomAD frequency: 0.00006  dbSNP: rs375626634

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000990204	SCV003915966	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 isoleucine with threonine at codon 3253 of the RYR1 protein, p.(Ile3253Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000201, a frequency consistent with pathogenicity for MHS. This variant has not to our knowledge been reported in any individuals with a personal history of an MH episode or a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. 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 0.845 supports neither a pathogenic nor a benign status for this variant. This variant has been classified a Variant of Unknown Significance. Criteria implemented: none.
Genetic Services Laboratory, University of Chicago	RCV000147452	SCV000194883	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000721757	SCV000852889	uncertain significance	not provided	2017-02-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000990204	SCV001141068	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122766	SCV001281524	uncertain significance	Central core myopathy	2017-04-27	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	RCV001122767	SCV001281525	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-04-27	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	RCV000990204	SCV001281526	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-04-27	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.
GeneDx	RCV000721757	SCV002015510	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in a patient with a clinical diagnosis of congenital myopathy; however, no further clinical or segregation information was provided (Galleni Leo et al., 2020); Identified in individuals with heat stroke (Schiermann et al., 2013) and malignant hyperthermia (Roux-Buisson et al., 2016), however was reported to not segregate with malignant hyperthermia in the family (Roux-Buisson et al., 2016); Reported in one affected individual and described as a likely pathogenic variant in association with exertional heat illness, myalgia and hyperCKemia (Gardner et al., 2020); 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: 28326467, 23035052, 26994242, 25637381, 30611313, 32054689, 23826317, 33458582)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850001	SCV002113276	likely pathogenic	RYR1-related disorder	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3253 of the RYR1 protein (p.Ile3253Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or central core myopathy (PMID: 23035052, 26994242, 32054689, 33458582). This variant has been reported in individual(s) with autosomal recessive congenital myopathy (PMID: 23826317); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 159865). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000721757	SCV003815013	uncertain significance	not provided	2022-04-29	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001122766	SCV004047701	uncertain significance	Central core myopathy		criteria provided, single submitter	clinical testing	The missense variant c.9758T>C (p.Ile3253Thr) in RYR1 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS), but no details are available for independent assessment. It has not been reported in affected individuals. This p.Ile3253Thr variant has allele frequency 0.0036% in the gnomad and novel (not in any individuals) in 1000 genome database. The amino acid Ile at position 3253 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile3253Thr in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
All of Us Research Program, National Institutes of Health	RCV000990204	SCV004820960	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 3253 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with malignant hyperthermia susceptibility (PMID: 23035052, 25658027, 26994242). This variant has been identified in 10/280974 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	RCV000148825	SCV000190564	uncertain significance	Congenital myopathy	2014-06-01	no assertion criteria provided	research