ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4236C>G (p.His1412Gln)

gnomAD frequency: 0.00005  dbSNP: rs146206507
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000414772 SCV000492924 uncertain significance Congenital myasthenic syndrome 2015-01-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000721526 SCV000852609 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198359 SCV001369267 uncertain significance Congenital myopathy with fiber type disproportion 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001214098 SCV001385763 uncertain significance RYR1-related disorder 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1412 of the RYR1 protein (p.His1412Gln). This variant is present in population databases (rs146206507, gnomAD 0.009%). 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: 374136). 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.
GeneDx RCV000721526 SCV001819109 uncertain significance not provided 2022-02-18 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported previously in a case control series of individuals with inherited peripheral neuropathies, although it is not clear if this variant was detected in an affected individual or in a control (Shabhuttl et al., 2014); This variant is associated with the following publications: (PMID: 24627108)
Fulgent Genetics, Fulgent Genetics RCV002481286 SCV002791261 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 2021-08-24 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000721526 SCV003812580 uncertain significance not provided 2020-01-14 criteria provided, single submitter clinical testing

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