Submissions for variant NM_000540.3(RYR1):c.2603G>A (p.Arg868His)

gnomAD frequency: 0.00006  dbSNP: rs750938678

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486594	SCV000567556	uncertain significance	not specified	2017-03-27	criteria provided, single submitter	clinical testing	The R868H variant has been previously reported in an individual with central core disease, however, this variant was noted to be inherited from an asymptomatic parent (Snoeck et al., 2015). The R868H variant is observed in 43/16330 (0.26%) alleles from individuals of South Asian background in large population cohorts, and 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082475	SCV000777544	likely benign	RYR1-related disorder	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001124718	SCV001283703	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-08-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001124719	SCV001283704	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-08-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000486594	SCV001423022	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Arg868His variant in RYR1 has been reported in one individual with Central Core Disease, the individual's asymptomatic parent, and 1 homozygous individual undergoing genetic testing through GeneDx (PMID: 25960145; Variation ID: 419631), and has been identified in 0.2614% (80/30610) of South Asian chromosomes, 0.2258% (80/35428) of Latino chromosomes, and 0.002327% (3/128944) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750938678). This variant has also been reported as a VUS and likely benign variant in ClinVar (Variation ID: 419631). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Arg868Cys, has been reported as a VUS in association with disease in ClinVar (Variation ID: 590504). In summary, while the clinical significance of the p.Arg868His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015).
Revvity Omics, Revvity	RCV000721464	SCV003812500	likely benign	not provided	2023-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000486594	SCV005394559	likely benign	not specified	2024-09-12	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.2603G>A (p.Arg868His) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 250922 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Myopathy, RYR1-Associated phenotype. c.2603G>A has been reported in the literature in one individual affected with Myopathy, RYR1-Associated (Snoeck_2015). These report does not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36983702, 25960145). ClinVar contains an entry for this variant (Variation ID: 419631). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000721464	SCV005408804	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001082475	SCV000852534	uncertain significance	RYR1-related disorder	2024-04-05	no assertion criteria provided	clinical testing	The RYR1 c.2603G>A variant is predicted to result in the amino acid substitution p.Arg868His. This variant has been previously reported as a variant of uncertain significance in single patient with central core disease, but the variant was also found heterozygous in the asymptomatic parent (Snoeck et al. 2015. PubMed ID: 25960145). The c.2603G>A variant has an allele frequency of 0.26% in individuals of South Asian descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/419631/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.