Submissions for variant NM_000540.3(RYR1):c.7036G>A (p.Val2346Met)

gnomAD frequency: 0.00001  dbSNP: rs193922799

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580429	SCV001810116	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-28	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 valine with methionine at codon 2346 of the RYR1 protein, p.(Val2346Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; both of these individuals had 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), however, these individuals were not counted for PS4 as they have a second RYR1 variant phase unknown (PMID:16163667, PMID:30236257). 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 >0.85 (0.944) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate.
AiLife Diagnostics, AiLife Diagnostics	RCV000119678	SCV002502843	likely pathogenic	not provided	2022-01-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514604	SCV003443246	uncertain significance	RYR1-related disorder	2022-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2346 of the RYR1 protein (p.Val2346Met). This variant is present in population databases (rs193922799, gnomAD 0.003%). This missense change has been observed in individual(s) with RYR1-related conditions (PMID: 14985404). ClinVar contains an entry for this variant (Variation ID: 133179). 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. 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.
GeneDx	RCV000119678	SCV004040456	likely pathogenic	not provided	2025-04-03	criteria provided, single submitter	clinical testing	Previously reported in an individual with muscle rigidity, elevated CK levels, MHS confirmed by IVCT and muscle biopsy evidence of core myopathy; a second RYR1 variant was also identified, however segregation studies were not reported (PMID: 14985404); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16163667, 31165076, 19825159, 26119398, 14985404, 12668474, 33767344, 30236257, 39745345)
Baylor Genetics	RCV001580429	SCV004041475	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-02-21	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001580429	SCV005416444	likely pathogenic	Malignant hyperthermia, susceptibility to, 1		criteria provided, single submitter	clinical testing	PS4_Moderate+PM1+PP3_Moderate
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798782	SCV005420578	likely pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2024-10-04	criteria provided, single submitter	research	PM1,PM2,PM5,PP3
RYR1 database	RCV000119678	SCV000154585	not provided	not provided		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000119678	SCV002036236	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000119678	SCV002037444	uncertain significance	not provided		no assertion criteria provided	clinical testing