Submissions for variant NM_000540.3(RYR1):c.13480G>A (p.Glu4494Lys)

gnomAD frequency: 0.00009  dbSNP: rs143849895

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685680	SCV000813170	uncertain significance	RYR1-related disorder	2022-03-15	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 4494 of the RYR1 protein (p.Glu4494Lys). This variant is present in population databases (rs143849895, gnomAD 0.004%). 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: 565982). 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.
GeneDx	RCV001566937	SCV001790528	uncertain significance	not provided	2020-01-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002493139	SCV002784674	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	2021-10-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001566937	SCV003812474	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004231	SCV004816235	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 4494 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 in the literature. This variant has been identified in 9/265396 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.
Ambry Genetics	RCV004026207	SCV004945812	uncertain significance	Inborn genetic diseases	2023-10-05	criteria provided, single submitter	clinical testing	The c.13480G>A (p.E4494K) alteration is located in exon 92 (coding exon 92) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 13480, causing the glutamic acid (E) at amino acid position 4494 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.