Submissions for variant NM_000540.3(RYR1):c.12355A>T (p.Asn4119Tyr)

gnomAD frequency: 0.00002  dbSNP: rs193922848

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001449991	SCV001653541	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 asparagine with tyrosine at codon 4119 of the RYR1 protein, p.(Asn4119Tyr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000016, 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), PS4_Supporting (PMID:15731587). A functional study using [3H]ryanodine in HEK293 cells showed altered activity of this variant compared to wild-type but this study did not meet the VCEP criteria for a well-established functional study (PMID:27558158). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.813 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.
Invitae	RCV001302437	SCV001491646	uncertain significance	RYR1-related disorder	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 4119 of the RYR1 protein (p.Asn4119Tyr). This variant is present in population databases (rs193922848, gnomAD 0.002%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 15731587). This variant is also known as N4120Y. ClinVar contains an entry for this variant (Variation ID: 133036). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change does not substantially affect RYR1 function (PMID: 27558158). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483204	SCV002790394	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119459	SCV003812544	uncertain significance	not provided	2019-12-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000119459	SCV004031814	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	Published functional studies found this variant was associated with calcium and magnesium dependent channel regulation that was not significantly different than wild-type (Gomez AC et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(N4120Y); This variant is associated with the following publications: (PMID: 15731587, 16115682, 27558158)
All of Us Research Program, National Institutes of Health	RCV001449991	SCV004816224	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 4119 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 in HEK293 cells showed no significant difference between Ca2+-channel regulation in cells expressing this variant compared to cells expressing wild-type RYR1 (PMID: 27558158). This variant has been reported in one individual affected with malignant hyperthermia susceptibility (PMID: 15731587). This variant has been identified in 2/281334 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.
Leiden Muscular Dystrophy (RYR1)	RCV000119459	SCV000154366	not provided	not provided		no assertion provided	not provided