Submissions for variant NM_000540.3(RYR1):c.2275A>G (p.Asn759Asp)

gnomAD frequency: 0.00014  dbSNP: rs147320363

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723802	SCV000203450	uncertain significance	not provided	2014-01-06	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210004	SCV000265693	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
GeneDx	RCV000723802	SCV000514423	uncertain significance	not provided	2018-11-26	criteria provided, single submitter	clinical testing	The N759D variant in the RYR1 gene has been identified in trans with another variant in a patient with central core disease (Bharucha-Goebel et al., 2013; Amburgey et al., 2013). However, the N759D variant has also been detected in the heterozygous state in individuals with no personal or family history of malignant hyperthermia or myopathy (Gonsalves et al., 2013). The N759D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N759D 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000153861	SCV000540250	uncertain significance	not specified	2016-03-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Limited reports in probands, reported in unaffected individuals; ExAC: 16/66720 European; ClinVar: 2 VUS
Invitae	RCV000533102	SCV000659885	likely pathogenic	RYR1-Related Disorders	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 759 of the RYR1 protein (p.Asn759Asp). This variant is present in population databases (rs147320363, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive central core myopathy (PMID: 23553484). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 161369). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000723802	SCV001151816	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000210004	SCV002761540	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2021-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492546	SCV002782029	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	2021-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514856	SCV003702333	uncertain significance	Inborn genetic diseases	2022-08-29	criteria provided, single submitter	clinical testing	The c.2275A>G (p.N759D) alteration is located in exon 19 (coding exon 19) of the RYR1 gene. This alteration results from an A to G substitution at nucleotide position 2275, causing the asparagine (N) at amino acid position 759 to be replaced by an aspartic acid (D). Based on data from gnomAD, the G allele has an overall frequency of 0.01% (38/282814) total alleles studied. This alteration was detected in a compound heterozygous state with the RYR1 c.14422_14424delTTC (p.F4808del) alteration in an individual with central core disease. Clinical features included no motor ability, weakness, contractures, respiratory distress, and feeding difficulties (Amburgey, 2013; Bharucha-Goebel, 2013). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000723802	SCV003814455	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000723802	SCV004224621	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PP3
Color Diagnostics, LLC DBA Color Health	RCV000210004	SCV004357292	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 759 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, though it has been reported in individuals affected with myopathy (PMID: 23553484). This variant has been identified in 38/282814 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.
PreventionGenetics, part of Exact Sciences	RCV003905277	SCV004726477	uncertain significance	RYR1-related condition	2023-12-06	criteria provided, single submitter	clinical testing	The RYR1 c.2275A>G variant is predicted to result in the amino acid substitution p.Asn759Asp. This variant has been reported in the compound heterozygous state in an individual with RYR1-associated myopathy (Table 1, Bharucha-Goebel et al. 2013. PubMed ID: 23553484; Amburgey et al. 2013. PubMed ID: 23919265; Table S2 Olfson et al. 2015. PubMed ID: 26332594). This variant was also reported in an individual with no family history of malignant hyperthermia susceptibility, heat illness, or myopathy (Supp. Table 3 Gonsalves SG et al 2013. PubMed ID: 24195946). This variant is reported in 0.024% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CSER _CC_NCGL, University of Washington	RCV000148816	SCV000190555	uncertain significance	Myopathy, RYR1-associated	2014-06-01	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000723802	SCV001799892	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723802	SCV001965533	uncertain significance	not provided		no assertion criteria provided	clinical testing