ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.443C>T (p.Thr148Ile)

gnomAD frequency: 0.00061  dbSNP: rs151325948
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000721535 SCV000705066 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623845 SCV000741932 uncertain significance Inborn genetic diseases 2016-11-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000818782 SCV000959414 uncertain significance RYR1-related disorder 2022-10-21 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 148 of the RYR1 protein (p.Thr148Ile). This variant is present in population databases (rs151325948, gnomAD 0.2%). 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: 499535). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. 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 RCV000721535 SCV001776591 uncertain significance not provided 2024-07-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33767344, 32236737)
Fulgent Genetics, Fulgent Genetics RCV002497264 SCV002814322 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 2022-02-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000721535 SCV003810547 uncertain significance not provided 2023-04-10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003514380 SCV004357262 likely benign Malignant hyperthermia, susceptibility to, 1 2022-08-04 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000721535 SCV005194577 uncertain significance not provided criteria provided, single submitter not provided
PreventionGenetics, part of Exact Sciences RCV000818782 SCV000852621 likely benign RYR1-related disorder 2023-06-16 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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