Submissions for variant NM_000540.3(RYR1):c.2383C>T (p.Arg795Cys)

gnomAD frequency: 0.00026  dbSNP: rs547608972

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530053	SCV000659888	uncertain significance	RYR1-related disorder	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 795 of the RYR1 protein (p.Arg795Cys). This variant is present in population databases (rs547608972, gnomAD 0.01%). 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: 478212). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662139	SCV000784482	uncertain significance	Central core myopathy	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662140	SCV000784483	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662141	SCV000784484	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662142	SCV000784485	uncertain significance	Congenital myopathy with fiber type disproportion	2018-03-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001797109	SCV002038921	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Etarhuni2024)
MGZ Medical Genetics Center	RCV000662139	SCV002580011	uncertain significance	Central core myopathy	2022-05-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002491117	SCV002799540	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
Revvity Omics, Revvity	RCV001797109	SCV003812479	uncertain significance	not provided	2021-08-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001797109	SCV004141585	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	RYR1: PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701652	SCV005202841	uncertain significance	not specified	2024-07-24	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.2383C>T (p.Arg795Cys) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251486 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. To our knowledge, no occurrence of c.2383C>T 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: 478212). Based on the evidence outlined above, the variant was classified as uncertain significance.