Submissions for variant NM_000540.3(RYR1):c.1936A>C (p.Asn646His)

dbSNP: rs1064796780

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484381	SCV000573847	uncertain significance	not provided	2017-03-03	criteria provided, single submitter	clinical testing	The N646H variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N646H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N646H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N646H as a variant of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004003406	SCV004825715	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 646 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.