ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14270G>A (p.Arg4757His) (rs768360593)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV001450014 SCV001653564 uncertain significance Malignant hyperthermia susceptibility 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 4757 of the RYR1 protein, p.(Arg4757His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000159, 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. 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 <0.50 (0.452) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, BP4.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000721359 SCV000339056 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000293888 SCV000413016 uncertain significance Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000351106 SCV000413017 uncertain significance Malignant hyperthermia, susceptibility to, 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000389289 SCV000413018 uncertain significance Minicore myopathy with external ophthalmoplegia 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000287938 SCV000413019 uncertain significance Central core myopathy 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000721359 SCV000576933 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing The R4757H variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R4757H variant is observed in 18/111538 (0.016%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The R4757H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R4757H as a variant of uncertain significance.
Invitae RCV000539271 SCV000659843 likely benign RYR1-Related Disorders 2020-08-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000721359 SCV000852400 uncertain significance not provided 2013-10-30 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000721359 SCV001715523 uncertain significance not provided 2020-11-17 criteria provided, single submitter clinical testing

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