Submissions for variant NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met)

gnomAD frequency: 0.00004  dbSNP: rs118192140

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001129440	SCV002570145	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 threonine with methionine at codon 4709 of the RYR1 protein, p.(Thr4709Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with recessive myopathies (PMID:17033962, PMID:21062345, PMID:22473935). A knock-in mouse model does not demonstrate a response to isoflurane in the heterozygous state, this is considered evidence against pathogenicity for autosomal dominantly inherited MH, BS_Supporting (PMID:31107960). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate, BS3_Supporting.
Baylor Genetics	RCV000191124	SCV000245531	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2013-12-23	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [R2241X] in a 25-year-old female with motor delays, tinnitus, vertigo, central hypotonia, peripheral hypertonia, pes cavus, dysmorphisms, microcephaly, ophthalmoplegia, supraventricular tachycardia, scoliosis, lordosis
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555087	SCV000659841	pathogenic	RYR1-related disorder	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4709 of the RYR1 protein (p.Thr4709Met). This variant is present in population databases (rs118192140, gnomAD 0.09%). This missense change has been observed in individuals with autosomal recessive congenital myopathy (PMID: 17483490, 23919265, 31055738; Invitae). ClinVar contains an entry for this variant (Variation ID: 65996). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 1743490). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000119498	SCV000852388	pathogenic	not provided	2018-03-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763429	SCV000894194	likely pathogenic	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
Illumina Laboratory Services, Illumina	RCV000555087	SCV000915831	likely pathogenic	RYR1-related disorder	2018-11-12	criteria provided, single submitter	clinical testing	The RYR1 c.14126C>T (p.Thr4709Met) variant has been reported in at least five studies and is found in a total of five patients with RYR1-related disorders including central code disease, multiminicore disease, and neuromuscular disease including four in a compound heterozygous state and one in a heterozygous state (Zhou et al. 2007; Bevilacqua et al. 2011; Amburgey et al. 2013; Vill et al. 2017; Todd et al. 2018). The p.Thr4709Met variant was absent from 300 controls and is reported at a frequency of 0.000888 in the Ashkenazi Jewish population of the Genome Aggregation Database. Zhou et al. (2007) demonstrated greatly reduced levels of RYR1 protein in skeletal muscles of patients in whom the p.Thr4709Met heterozygous variant was expressed in the background of a second non-transcribed allele. Based on the evidence, the p.Thr4709Met variant is classified as likely pathogenic RYR1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001129440	SCV001288966	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). 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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814038	SCV001755206	likely pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000119498	SCV001780073	pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Reported as a putative dominant variant but inheritance uncertain in a patient with features of of an RYR1-related myopathy who also had other variants in the RYR1 gene, without clear segregation information (Zhou et al., 2007; Klein et al., 2012); Published functional studies demonstrate decreased protein expression compared to controls in muscle and monoallelic expression of the T4709M allele, suggesting epigenetic silencing of the other RYR1 allele in an affected individual (Zhou et al., 2007); 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, 17483490, 22473935, 23919265, 26633545, 30611313, 17033962, 32403337, 31980526, 33087929, 21062345, 31107960)
Suma Genomics	RCV002262610	SCV002543787	likely pathogenic	Central core myopathy; Congenital multicore myopathy with external ophthalmoplegia		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119498	SCV003827260	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224129	SCV003920406	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2021-03-30	criteria provided, single submitter	clinical testing	RYR1 NM_000540.2 exon 96 p.Thr4709Met (c.14126C>T): This variant has been reported in the literature in the compound heterozygous state or with monoallelic expression in at least 3 individuals with congenital myopathies (Zhou 2007 PMID:17483490, Bevilacqua 2011 PMID:21062345, Amburgey 2013 PMID:23919265). This variant is present in 0.08% (9/10346) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-39063944-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:65996). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, western blot studies on skeletal muscle tissue have demonstrated decreased protein expression, further supporting a deleterious effect of this variant (Zhou 2007 PMID:17483490). In summary, this variant is classified as pathogenic based on the data above.
All of Us Research Program, National Institutes of Health	RCV001129440	SCV004816257	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 4709 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). A functional study using genetically engineered mice showed that mice homozygous for this variant are hypersensitive to isoflurane and experience an increase in core body temperature similar to malignant hyperthermia susceptible mice, but at a slower rate. Further, the study showed that mice heterozygous for this variant were not hypersensitive to isoflurane and did not experience an increase in core temperature compared to wild-type mice (PMID: 31107960). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 65996). This variant has been identified in 12/281074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004586529	SCV005077883	likely pathogenic	Congenital myopathy	2024-06-19	criteria provided, single submitter	curation	The heterozygous p.Thr4709Met variant in RYR1 was identified by our study, in the compound heterozygous state, along with a likely pathogenic variant, in 1 individual with autosomal recessive congenital myopathy. The p.Thr4709Met variant in RYR1 has been reported in at least 2 individuals with congenital myopathy (PMID: 21062345, 30155738), and has been identified in 0.1% (29/29576) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192140). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 65996) and has been interpreted as pathogenic or likely pathogenic by multiple submitters for congenital myopathy, and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel. Of the 3 affected individuals, 3 were compound heterozygotes that carried reported pathogenic/likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Thr4709Met variant is pathogenic (PMID: 30155738). Animal models in mice have shown that this variant causes autosomal recessive congenital myopathy (PMID: 31107960). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in RYR1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive congenital myopathy. ACMG/AMP Criteria applied: PP3_moderate, PM3, PS3_moderate, PP2 (Richards 2015).
GeneReviews	RCV000056243	SCV000087332	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119498	SCV000154405	not provided	not provided		no assertion provided	not provided