ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6860C>A (p.Ala2287Asp)

gnomAD frequency: 0.00002  dbSNP: rs761154999
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001943281 SCV002182203 uncertain significance RYR1-related disorder 2025-01-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2287 of the RYR1 protein (p.Ala2287Asp). This variant is present in population databases (rs761154999, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 30611313). ClinVar contains an entry for this variant (Variation ID: 1412777). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002484475 SCV002779973 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 2021-07-27 criteria provided, single submitter clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire RCV004795346 SCV005045632 likely pathogenic Centronuclear myopathy 2024-03-01 criteria provided, single submitter research
GeneDx RCV004720975 SCV005327579 uncertain significance not provided 2024-03-07 criteria provided, single submitter clinical testing Reported with a second RYR1 variant on the opposite allele (in trans) in a patient with arthrogryposis, ophthalmoplegia, eyelid ptosis, muscle weakness, and lordosis (PMID: 30611313); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30611313, 12668474, 33767344)

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