Submissions for variant NM_000540.3(RYR1):c.1715A>C (p.Glu572Ala)

gnomAD frequency: 0.00001  dbSNP: rs779551357

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721424	SCV000852488	uncertain significance	not provided	2015-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV001052918	SCV001217153	uncertain significance	RYR1-related disorder	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 572 of the RYR1 protein (p.Glu572Ala). This variant is present in population databases (rs779551357, gnomAD 0.01%). 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: 590486). 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. 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.
GeneDx	RCV000721424	SCV001825749	uncertain significance	not provided	2021-02-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center	RCV002227492	SCV002506959	uncertain significance	Central core myopathy; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2021-06-04	criteria provided, single submitter	clinical testing	The inherited heterozygous c.1715A>C (p.Glu572Ala) missense variant identified in the RYR1 gene has not been reported in affected individuals in the literature. The variant has 0.00007424 allele frequency in the gnomAD(v2) database (21 out of 282850 heterozygous alleles, no homozygotes)suggesting it is not a common benign variant in the populations represented in that database. The variant has been reported in the ClinVar database as a variant of uncertain significance (Variation ID: 590486). The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools. Based on the available evidence, the inherited heterozygous c.1715A>C (p.Glu572Ala) missense variant identified in the RYR1 gene is reported as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002485819	SCV002787867	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	2021-08-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721424	SCV004236875	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999829	SCV004820752	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 572 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 malignant hyperthermia in the literature. This variant has been identified in 21/282850 chromosomes 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.