Submissions for variant NM_000540.3(RYR1):c.6910G>A (p.Gly2304Ser)

gnomAD frequency: 0.00005  dbSNP: rs377080876

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000353321	SCV000412382	uncertain significance	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000267871	SCV000412383	uncertain significance	Multiminicore myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000304664	SCV000412384	uncertain significance	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000359403	SCV000412385	uncertain significance	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000655539	SCV000777470	uncertain significance	RYR1-related disorder	2022-06-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2304 of the RYR1 protein (p.Gly2304Ser). This variant is present in population databases (rs377080876, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 329056). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV001577909	SCV001805398	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 16084090, 12668474)
Fulgent Genetics, Fulgent Genetics	RCV002487450	SCV002800172	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	2021-09-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001577909	SCV003814966	uncertain significance	not provided	2019-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021747	SCV004945844	uncertain significance	Inborn genetic diseases	2024-01-04	criteria provided, single submitter	clinical testing	The c.6910G>A (p.G2304S) alteration is located in exon 43 (coding exon 43) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 6910, causing the glycine (G) at amino acid position 2304 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.