Submissions for variant NM_000540.3(RYR1):c.2677G>A (p.Gly893Ser)

gnomAD frequency: 0.00202  dbSNP: rs147336515

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000990196	SCV000411950	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-05-29	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.
Illumina Laboratory Services, Illumina	RCV000260524	SCV000411951	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2018-05-29	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.
Illumina Laboratory Services, Illumina	RCV000334117	SCV000411952	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388593	SCV000411953	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000721467	SCV000521244	likely benign	not provided	2020-10-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23394784, 24055113, 22473935, 25637381, 26332594)
PreventionGenetics, part of Exact Sciences	RCV004528871	SCV000852537	likely benign	RYR1-related disorder	2019-06-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Eurofins Ntd Llc (ga)	RCV000427522	SCV000854893	likely benign	not specified	2017-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427522	SCV000918159	likely benign	not specified	2019-08-23	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.2677G>A (p.Gly893Ser) results in a non-conservative amino acid change located in the first Ryr domain (IPR003032) of the encoded protein sequence. Five of five 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 277800 control chromosomes, predominantly at a frequency of 0.007 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2500 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Central Core Disease phenotype (2.8e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2677G>A has been reported in the literature in individuals affected with myopathy (Klein_2012, Maggi_2013, Isackson_2018), however one of these patient's unaffected father also tested positive for this variant, supporting a benign role for the variant (Klein_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000990196	SCV001141055	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148791	SCV000190529	likely benign	Congenital myopathy	2014-06-01	no assertion criteria provided	research