ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.3556G>A (p.Gly1186Ser)

dbSNP: rs1568465251
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721502 SCV000852579 uncertain significance not provided 2018-02-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002499328 SCV002781587 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 2021-10-09 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002533064 SCV003761238 uncertain significance RYR1-related myopathy 2023-01-25 criteria provided, single submitter curation The heterozygous p.Gly1186Ser variant in RYR1 was identified by our study, in the compound heterozygous state with another variant of uncertain significance (ClinVar Variation ID: 1000892), in one individual with congenital myopathy. Familial segregation analysis revealed that this variant was in trans with another variant of uncertain significance (ClinVar Variation ID: 1000892). The p.Gly1186Ser variant in RYR1 has not been previously reported in individuals with RYR1-related myopathy. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID:590519) and has been interpreted as a variant of uncertain significance by Prevention Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly1186Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting (Richards 2015).
Invitae RCV003757201 SCV004524740 uncertain significance RYR1-related disorder 2023-08-17 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1186 of the RYR1 protein (p.Gly1186Ser). This variant also falls at the last nucleotide of exon 26, which is part of the consensus splice site for this exon. 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: 590519). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
All of Us Research Program, National Institutes of Health RCV003999840 SCV004826667 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-09-17 criteria provided, single submitter clinical testing This variant replaces glycine with serine at codon 1186 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). In addition, this variant alters the last c.G nucleotide of exon 26 and is predicted to disrupt RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has not been identified 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.

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