ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.9457G>A (p.Gly3153Arg)

gnomAD frequency: 0.00003  dbSNP: rs779410371
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541614 SCV000660092 uncertain significance RYR1-related disorder 2022-07-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3153 of the RYR1 protein (p.Gly3153Arg). This variant is present in population databases (rs779410371, gnomAD 0.007%). This missense change has been observed in individual(s) with congenital myopathy and/or malignant hyperthermia susceptibility (MHS) (PMID: 19191333, 25214167, 29417091). ClinVar contains an entry for this variant (Variation ID: 478300). 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 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.
3billion RCV002283490 SCV002573359 uncertain significance Central core myopathy 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV002497204 SCV002815027 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 2021-08-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999520 SCV004820952 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 3153 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to not segregate with malignant hyperthermia susceptibility in one study, where this variant was described as a potential polymorphism (PMID: 19191333). This variant has been reported in individuals with congenital myopathy (PMID: 25214167, 29417091). This variant has been identified in 4/248494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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