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

gnomAD frequency: 0.00007  dbSNP: rs138932463

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-09-23	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700389	SCV005203198	uncertain significance	not specified	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.12629A>G (p.Lys4210Arg) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 201352 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Myopathy, RYR1-Associated, allowing no conclusion about variant significance. c.12629A>G has been reported in the literature in individuals affected with multiminicore disease (Snoeck_2015, Rokach_2015). These data do not allow clear conclusion about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 26019235, 25960145). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 93246). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000534293	SCV005361640	uncertain significance	RYR1-related disorder	2024-08-23	no assertion criteria provided	clinical testing	The RYR1 c.12629A>G variant is predicted to result in the amino acid substitution p.Lys4210Arg. This variant was reported in one patient with multiminicore disease (Snoeck et al. 2015. PubMed ID: 25960145, see Patient #53 in Table 3), but this patient also had four other rare missense variants in RYR1, and so the effect of the c.12629A>G (p.Lys4210Arg) variant alone is difficult to discern. This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.