Submissions for variant NM_000540.3(RYR1):c.7844G>A (p.Arg2615His)

gnomAD frequency: 0.00005  dbSNP: rs145183043

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525755	SCV000660045	uncertain significance	RYR1-related disorder	2022-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2615 of the RYR1 protein (p.Arg2615His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of congenital myopathy (PMID: 32403337). ClinVar contains an entry for this variant (Variation ID: 478280). 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.
PreventionGenetics, part of Exact Sciences	RCV000721676	SCV000852803	uncertain significance	not provided	2015-08-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483519	SCV002786100	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	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000721676	SCV004021631	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	Observed in patient with congenital axial hypotonia and normal serum CK in published literature (Gonzalez-Quereda et al., 2020); however, no further clinical information was provided.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32403337)
Revvity Omics, Revvity	RCV000721676	SCV004236906	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999516	SCV004820928	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2615 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 been reported in an individual affected with congenital myopathy (PMID: 32403337). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000721676	SCV001551029	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RYR1 p.Arg2615His variant was not identified in the literature but was identified in dbSNP (ID: rs145183043) and ClinVar (classified as uncertain significance by Invitae and Prevention Genetics). The variant was identified in control databases in 21 of 280550 chromosomes at a frequency of 0.00007485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 6 of 24906 chromosomes (freq: 0.000241), East Asian in 3 of 19924 chromosomes (freq: 0.000151), Latino in 5 of 35422 chromosomes (freq: 0.000141), Other in 1 of 7210 chromosomes (freq: 0.000139), European (non-Finnish) in 5 of 128914 chromosomes (freq: 0.000039) and South Asian in 1 of 30610 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Arg2615 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.