ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13885G>A (p.Val4629Met)

gnomAD frequency: 0.00001  dbSNP: rs752668333
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001756659 SCV001986240 uncertain significance not provided 2021-04-15 criteria provided, single submitter clinical testing Reported previously as heterozygous in an individual with moderate clinical severity and mild facial weakness (Klein et al., 2011); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21911697, 25214167)
Fulgent Genetics, Fulgent Genetics RCV002477923 SCV002790660 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 2021-12-22 criteria provided, single submitter clinical testing
Invitae RCV003591888 SCV004285606 uncertain significance RYR1-related disorder 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4629 of the RYR1 protein (p.Val4629Met). This variant is present in population databases (rs752668333, gnomAD 0.0009%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 21911697, 25214167). ClinVar contains an entry for this variant (Variation ID: 1303160). 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.
All of Us Research Program, National Institutes of Health RCV004008982 SCV004816250 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-11-28 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 4629 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it has been reported in individuals affected with other phenotypes (PMID: 21911697, 25214167). This variant has been identified in 2/251476 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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