Submissions for variant NM_000540.3(RYR1):c.152C>A (p.Thr51Asn)

gnomAD frequency: 0.00006  dbSNP: rs193922749

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001123156	SCV001816201	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 Asparagine at codon 51 of the RYR1 protein, p.(Thr51Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00012 (15 alleles), 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:18564801 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. 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).This variant segregates with MHS in 1 individual (PMID:18564801). A REVEL score of 0.769 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.
Eurofins Ntd Llc (ga)	RCV000119572	SCV000203444	uncertain significance	not provided	2014-04-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797515	SCV000937075	uncertain significance	RYR1-related disorder	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 51 of the RYR1 protein (p.Thr51Asn). This variant is present in population databases (rs193922749, gnomAD 0.01%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 18564801, 37937776). ClinVar contains an entry for this variant (Variation ID: 133099). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. 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.
Illumina Laboratory Services, Illumina	RCV001123156	SCV001281966	likely benign	Malignant hyperthermia, susceptibility to, 1	2017-10-04	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001124242	SCV001283174	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-10-04	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.
Revvity Omics, Revvity	RCV000119572	SCV003810526	uncertain significance	not provided	2020-06-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001123156	SCV004820703	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 51 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in an individual affected with malignant hyperthermia susceptibility with a personal history of a malignant hyperthermia episode (PMID: 18564801). This variant has been identified in 15/274886 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.
RYR1 database	RCV000119572	SCV000154479	not provided	not provided		no assertion provided	not provided