ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6469G>A (p.Glu2157Lys)

gnomAD frequency: 0.00002  dbSNP: rs554066182
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532936 SCV000659994 uncertain significance RYR1-related disorder 2023-11-03 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 2157 of the RYR1 protein (p.Glu2157Lys). This variant is present in population databases (rs554066182, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 25214167). ClinVar contains an entry for this variant (Variation ID: 478257). 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 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.
CeGaT Center for Human Genetics Tuebingen RCV000996883 SCV001151854 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483518 SCV002787957 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 2021-08-18 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999509 SCV004820881 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 2157 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.6 < inconclusive < 0.85, 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 other phenotype(s) (PMID: 25214167). This variant has been identified in 4/250590 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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