Submissions for variant NM_000540.3(RYR1):c.7291G>T (p.Asp2431Tyr)

dbSNP: rs193922810

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001802868	SCV002047608	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-07	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 aspartic acid with tyrosine at codon 2431 of the RYR1 protein, p.(Asp2431Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three 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), PS4_Moderate (PMID:30236257, PMID:30115273). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:30115273). Another variant assessed as likely pathogenic occurs at this codon, p.(Asp2431Asn), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:30236257). A REVEL score >0.85 (0.964) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_Moderate.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197604	SCV001368383	likely pathogenic	Congenital myopathy with fiber type disproportion	2019-01-02	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM5,PP2,PP3,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216014	SCV001387786	pathogenic	RYR1-related disorder	2020-01-06	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 16917943, 19648156, 30236257). ClinVar contains an entry for this variant (Variation ID: 133195). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 2431 of the RYR1 protein (p.Asp2431Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant disrupts the p.Asp2431 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 11575529, 15448513, 16917943, 30236257), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. 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.
Molecular Genetics, Royal Melbourne Hospital	RCV001802868	SCV002503772	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace aspartic acid with tyrosine at codon 2431 of the RYR1 protein (p.(Asp2431Tyr)). The aspartic acid residue is invariant across species (100 vertebrates, UCSC), and there is a large physicochemical difference between aspartic acid and tyrosine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.0). The prevalence of the variant in an affected cohort is significantly increased compared with the prevalence of a relevant low risk population (PMID: 30236257). The variant is associated with a clinical reaction consistent with malignant hyperthermia (MH) under anaesthesia and confirmed by a positive in vitro contracture tests, and segregates with MH susceptibility in multiple families (PMID: 19648156, 30115273, 30236257). A well-established in vitro functional study is supportive of a gain of function effect on intracellular calcium release for the variant (PMID: 30115273). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PM2, PP1, PP3, PP4.
GeneDx	RCV000119697	SCV002584373	likely pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest the variant caused an increased sensitivity to RYR1 agonists (Scheimann et al., 2018); 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: 19648156, 16917943, 12668474, 30115273, 30236257)
Leiden Muscular Dystrophy (RYR1)	RCV000119697	SCV000154604	not provided	not provided		no assertion provided	not provided