Submissions for variant NM_000540.3(RYR1):c.7034G>C (p.Ser2345Thr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593334	SCV004297334	uncertain significance	RYR1-related disorder	2023-05-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 2345 of the RYR1 protein (p.Ser2345Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with idiopathic hyper CK-emia and/or malignant hyperthermia susceptibility (PMID: 24433488, 26119398; Invitae). 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. This variant disrupts the p.Ser2345 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25960145, 31165076). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.