Submissions for variant NM_000540.3(RYR1):c.5000G>A (p.Arg1667His)

gnomAD frequency: 0.00022  dbSNP: rs138978909

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414466	SCV000492295	uncertain significance	not specified	2016-12-13	criteria provided, single submitter	clinical testing	The R1667H variant in the RYR1 gene has not been reported previously as a germline pathogenic variant, nor as a benign variant, to our knowledge. The R1667H variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1667H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1667H as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543824	SCV000659952	uncertain significance	RYR1-related disorder	2022-10-07	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 1667 of the RYR1 protein (p.Arg1667His). This variant is present in population databases (rs138978909, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions and/or malignant hyperthermia susceptibility (PMID: 28259615, 33564012, 34008892). ClinVar contains an entry for this variant (Variation ID: 373680). 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 not 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626708	SCV000747411	uncertain significance	Elevated circulating creatine kinase concentration; Myalgia; Exercise-induced myalgia	2017-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000543824	SCV000852664	uncertain significance	RYR1-related disorder	2023-12-19	criteria provided, single submitter	clinical testing	The RYR1 c.5000G>A variant is predicted to result in the amino acid substitution p.Arg1667His. This variant was reported in individuals with malignant hyperthermia (Levano et al. 2017. PubMed ID: 28259615; Hoppe et al. 2021. PubMed ID: 33564012). This variant was also documented in the compound heterozygous state in an individual with a congenital neuromuscular disease phenotype (Table S3, Marinakis et al. 2021. PubMed ID: 34008892). This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Illumina Laboratory Services, Illumina	RCV001126614	SCV001285834	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001126615	SCV001285835	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196458	SCV001367066	uncertain significance	Congenital myopathy with fiber type disproportion	2019-03-18	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000721573	SCV001747918	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481283	SCV002784050	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	2021-08-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721573	SCV003820577	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414466	SCV004803870	uncertain significance	not specified	2024-01-19	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.5000G>A (p.Arg1667His) results in a non-conservative amino acid change located in the Ryanodine receptor, junctional solenoid domain (IPR048581) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 246574 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. c.5000G>A has been reported in cis with a VUS variant p.Gly422Arg and in trans with an apparently pathogenic p.Leu417Pro in a female patient with Neuromuscular abnormalities through WES (example, Marinakis_2021). It has also been reported in a patient with unknown genetic condition (Levano_2017). These data do not allow any conclusion about variant significance. 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: 28259615, 34008892). ClinVar contains an entry for this variant (Variation ID: 373680, All VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001126614	SCV004820850	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1667 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 28259615). This variant has been identified in 41/277940 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.