ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.9892G>A (p.Ala3298Thr)

gnomAD frequency: 0.00002  dbSNP: rs544339193
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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 RCV000721762 SCV000852897 uncertain significance not provided 2017-09-11 criteria provided, single submitter clinical testing
Invitae RCV001312367 SCV001502816 likely pathogenic RYR1-related disorder 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3298 of the RYR1 protein (p.Ala3298Thr). This variant is present in population databases (rs544339193, gnomAD 0.05%). This missense change has been observed in individuals with autosomal recessive congenital myopathy (PMID: 28818389, 30611313; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 590640). 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 with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002485830 SCV002787777 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 2021-11-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000721762 SCV003810559 uncertain significance not provided 2023-10-09 criteria provided, single submitter clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire RCV004586902 SCV005038486 likely pathogenic Centronuclear myopathy 2024-03-01 criteria provided, single submitter research PM2+PM3+PP1+PP2

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