ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.11269A>G (p.Met3757Val)

gnomAD frequency: 0.00005  dbSNP: rs189249768
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001248213 SCV001421683 uncertain significance RYR1-Related Disorders 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3757 of the RYR1 protein (p.Met3757Val). This variant is present in population databases (rs189249768, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 972231). 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 not expected to disrupt RYR1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252343 SCV002523451 uncertain significance See cases 2020-01-03 criteria provided, single submitter clinical testing ACMG classification criteria: PM2
Fulgent Genetics, Fulgent Genetics RCV002484395 SCV002785845 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 2021-09-14 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003130232 SCV003812456 uncertain significance not provided 2021-11-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323832 SCV004028793 uncertain significance not specified 2023-07-21 criteria provided, single submitter clinical testing Variant summary: RYR1 c.11269A>G (p.Met3757Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250684 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (4.8e-05 vs 8.8e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.11269A>G in individuals affected with Malignant Hyperthermia Susceptibility and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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