ClinVar Genomic variation as it relates to human health

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 Methionine with Valine at codon 485 of the RYR1 protein, p.(Met485Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00061, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with central core disease and other myopathies inherited in a recessive pattern. No functional studies were identified for this variant that fulfilled the criteria for functional data as put forth by the ClinGen RYR1 VCEP for MHS (one study tested this variant in myotubes in the presence of other variants (PMID:16940308)). 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 of 0.551 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.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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.

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP1,BP6.

This missense variant replaces methionine with valine at codon 485 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies using patient-derived myotubes were inconclusive regarding this variant's impact on sensitivity to RYR1 agonists (PMID: 16940308, 18171678). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it has been observed in individuals affected with other conditions (ClinVar Variation ID: 133076). This variant has been identified in 95/282844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

RYR1: PM2

Converted during submission to Benign.

The RYR1 c.1453A>G variant is predicted to result in the amino acid substitution p.Met485Val. This variant has been reported in individuals with autosomal core myopathy; however, some of these reports show that this variant is in cis with the pathogenic variant c.325C>T (p.Arg109Trp) or is a third RYR1 variant with unknown phasing (Zhou et al.. 2006. PubMed ID: 16940308; Matthews et al. 2018. PubMed ID: 29298851; Gonsalves et al. 2013. PubMed ID: 24195946). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpreted as Uncertain significance and reported on 08-20-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.