Submissions for variant NM_000540.3(RYR1):c.1735G>A (p.Glu579Lys)

gnomAD frequency: 0.00004  dbSNP: rs753907367

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000721425	SCV000617872	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707225	SCV000836313	uncertain significance	RYR1-related disorder	2022-10-05	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 579 of the RYR1 protein (p.Glu579Lys). This variant is present in population databases (rs753907367, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449573). 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.
PreventionGenetics, part of Exact Sciences	RCV000707225	SCV000852489	uncertain significance	RYR1-related disorder	2024-01-23	criteria provided, single submitter	clinical testing	The RYR1 c.1735G>A variant is predicted to result in the amino acid substitution p.Glu579Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0077% 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.
CeGaT Center for Human Genetics Tuebingen	RCV000721425	SCV002543916	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	RYR1: PP3
Fulgent Genetics, Fulgent Genetics	RCV002497012	SCV002787981	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	2021-08-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721425	SCV003813168	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003603	SCV004820753	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 579 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 10/282840 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.