Submissions for variant NM_000540.3(RYR1):c.13180G>A (p.Glu4394Lys)

gnomAD frequency: 0.00002  dbSNP: rs748844266

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721305	SCV000852335	uncertain significance	not provided	2013-10-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001362581	SCV001558608	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 4394 of the RYR1 protein (p.Glu4394Lys). This variant is present in population databases (rs748844266, gnomAD 0.05%). 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: 590424). 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	RCV002507264	SCV002816944	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	2021-07-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721305	SCV003813081	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000721305	SCV004183653	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	RYR1: PP3, BS2
Ambry Genetics	RCV004026924	SCV004945809	uncertain significance	Inborn genetic diseases	2022-02-02	criteria provided, single submitter	clinical testing	The c.13180G>A (p.E4394K) alteration is located in exon 91 (coding exon 91) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 13180, causing the glutamic acid (E) at amino acid position 4394 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702371	SCV005204358	uncertain significance	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.13180G>A (p.Glu4394Lys) results in a conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 100790 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Myopathy, RYR1-Associated, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.13180G>A in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 590424). Based on the evidence outlined above, the variant was classified as uncertain significance.