Submissions for variant NM_000540.3(RYR1):c.14168G>A (p.Arg4723His)

gnomAD frequency: 0.00007  dbSNP: rs200766617

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001450013	SCV001653563	likely benign	Malignant hyperthermia of anesthesia	2021-03-16	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 4723 of the RYR1 protein, p.(Arg4723His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000325, 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. This variant was also identified in a relative with negative IVCT/CHCT results, BS2_Moderate. 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_Sup (PMID: 21118704). A REVEL score of 0.79 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PM1_Supporting, BS2_Moderate.
Invitae	RCV001053142	SCV001217389	uncertain significance	RYR1-Related Disorders	2022-07-19	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 4723 of the RYR1 protein (p.Arg4723His). This variant is present in population databases (rs200766617, gnomAD 0.03%). This missense change has been observed in individual(s) with clinically suspected malignant hyperthermia (PMID: 25658027). ClinVar contains an entry for this variant (Variation ID: 849226). 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	RCV002508283	SCV002817760	uncertain significance	not provided	2022-06-28	criteria provided, single submitter	clinical testing	Identified heterozygous in a patient with suspected malignant hyperthermia in published literature; however, variant was also present in patient's unaffected child (Fiszer et al., 2015); 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: 25658027)