ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.668A>G (p.His223Arg)

gnomAD frequency: 0.00001  dbSNP: rs766836202
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000996855 SCV001151804 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Invitae RCV001215577 SCV001387329 uncertain significance RYR1-related disorder 2022-04-22 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 223 of the RYR1 protein (p.His223Arg). This variant is present in population databases (rs766836202, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital myopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 808528). 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.
Fulgent Genetics, Fulgent Genetics RCV002481782 SCV002783754 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 2022-01-11 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004442 SCV004815853 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 223 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). his variant occurs in the N-terminal region (a.a. 1-552) of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). 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 with other phenotype(s) (Clinvar Variation ID: 808528; PMID: 33037202). This variant has been identified in 4/282866 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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