Submissions for variant NM_000540.3(RYR1):c.12629A>G (p.Lys4210Arg)

gnomAD frequency: 0.00007  dbSNP: rs138932463

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079123	SCV000110992	uncertain significance	not provided	2013-09-12	criteria provided, single submitter	clinical testing
Invitae	RCV000534293	SCV000659794	uncertain significance	RYR1-related disorder	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 4210 of the RYR1 protein (p.Lys4210Arg). This variant is present in population databases (rs138932463, gnomAD 0.02%). This missense change has been observed in individual(s) with multiminicore disease (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 93246). 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. 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	RCV002477225	SCV000895201	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	2021-07-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000079123	SCV002576254	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Reported previously in association with RYR1-related disorders in patients harboring additional RYR1 variants (Snoeck et al., 2015; Rokach et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26019235, 25960145)
Revvity Omics, Revvity	RCV000079123	SCV003813149	uncertain significance	not provided	2023-12-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997197	SCV004816230	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 4210 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia susceptibility in the literature. This variant has been observed in individuals with multimini-core disease case (PMID: 25960145) and congenital myopathy (PMID: 26019235). This variant has been identified in 23/232710 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.