ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4270G>A (p.Glu1424Lys)

gnomAD frequency: 0.00004  dbSNP: rs543630280
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721531 SCV000852614 uncertain significance not provided 2017-10-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485825 SCV002789542 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 2021-09-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535007 SCV003272514 uncertain significance RYR1-related disorder 2022-08-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1424 of the RYR1 protein (p.Glu1424Lys). This variant is present in population databases (rs543630280, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of malignant hyperthermia susceptibility (PMID: 31559918). ClinVar contains an entry for this variant (Variation ID: 590530). 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. 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.

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