Submissions for variant NM_000540.3(RYR1):c.7045A>T (p.Asn2349Tyr)

gnomAD frequency: 0.00001  dbSNP: rs780437705

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001904693	SCV002123158	uncertain significance	RYR1-related disorder	2021-08-18	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt RYR1 protein function. This sequence change replaces asparagine with tyrosine at codon 2349 of the RYR1 protein (p.Asn2349Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs780437705, ExAC 0.01%). This missense change has been observed in individual(s) with RYR1-related conditions (Invitae).