ClinVar Genomic variation as it relates to human health

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

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 2454 of the RYR1 protein, p.(Arg2454His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in 34 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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 (PMID: 30236257, 12059893, 16163667, 24433488, 11575529, 10051009, 10823104, 17081152, 20618998, 21455645, 23460944, 23558838, 25960145). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID: 19191333). 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 at least 11 individuals/families PP1_Strong (PMID: 12059893, 10051009). A REVEL score >0.85 (0.923) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.

This c.7361G>A (p.Arg2454His) variant in exon 46 of the RYR1 gene has been reported in multiple individuals with susceptibility to malignant hyperthermia that was diagnosed either by a well-defined laboratory diagnostic test or patients developed malignant hyperthermia crisis during anesthesia (PMID: 16163667, 19648156, 10051009, 20301565). Independently performed functional assays also support the pathogenicity of this variant (PMID, 19191333, 16163667, 27586648). Moreover, European Malignant Hyperthermia Group (EMHG) has categorized this variant as diagnostic for susceptibility to malignant hyperthermia https://emhg.org/genetics/mutations-in-ryr1/. The c.7361G>A (p.Arg2454His) variant in the RYR1 gene is classified as pathogenic .

This missense variant replaces arginine with histidine at codon 2454 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 has shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 25 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 12709367, 15448513, 16163667, 17081152, 19648156, 20681998, 21455645, 24433488, 25960145, 26951757) and has been reported to segregate with disease in over ten families (PMID: 30236257). This variant has been identified in 2/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2454 of the RYR1 protein (p.Arg2454His). This variant is present in population databases (rs118192122, gnomAD 0.007%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (MHS) (PMID: 10051009, 12059893, 19191333, 19648156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65980). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 19191333, 19648156). This variant disrupts the p.Arg2454 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612851, 12411788, 16163667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces arginine with histidine at codon 2454 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 has shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 25 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 12709367, 15448513, 16163667, 17081152, 19648156, 20681998, 21455645, 24433488, 25960145, 26951757) and has been reported to segregate with disease in over ten families (PMID: 30236257). This variant has been identified in 2/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Variant summary: RYR1 c.7361G>A (p.Arg2454His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251210 control chromosomes. c.7361G>A has been reported in the literature in the heterozygous state in multiple individuals affected with autosomal dominant Malignant Hyperthermia Susceptibility (example, Barone_1999, Carpenter_2009, Miller_2018), and segregated with disease among several related individuals. These data indicate that the variant is very likely to be associated with disease. Multiple functional studies have shown this variant causes enhanced ryanodine binding and decreased the Ca2+ threshold required for spontaneous muscle contraction (example, Chen_2017, Murayama_2016). The following publications have been ascertained in the context of this evaluation (PMID: 10051009, 19648156, 28687594, 30236257, 27586648). ClinVar contains an entry for this variant (Variation ID: 65980). Based on the evidence outlined above, the variant was classified as pathogenic.

Reported previously, in the heterozygous state, as a pathogenic variant associated with malignant hyperthermia (PMID: 10051009, 12059893, 19648156); B-lymphocytes from individuals with the R2454H variant displayed an increased extracellular acidification rate compared with wild-type cells, suggesting that the R2454H variant causes increased calcium channel activity (PMID: 19191333); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28325813, 26951757, 19648156, 31206373, 34462577, 19191333, 27586648, 28682948, 28687594, 12059893, 30236257, 30499100, 30788618, 32174957, 31447099, 17081152, 37937776, 10051009, 12668474, 33767344)

Converted during submission to Pathogenic.

The variant NM_000540.3:c.7361G>A (chr19:38500643) in RYR1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic and is one of the diagnostic MH variants (https://www.emhg.org/diagnostic-mutations). Based on ACMG criteria (PS3, PM2, PP3, PP4, PP5_Strong) this variant classifies as pathogenic.