Submissions for variant NM_000540.3(RYR1):c.11049GGA[4] (p.Glu3689del)

dbSNP: rs760784102

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203026	SCV000257710	uncertain significance	Malignant hypothermia	2015-04-17	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210002	SCV000265756	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
GeneDx	RCV000767095	SCV000617889	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Identified as a heterozygous variant in a cohort of African American men with muscle cramps and pain with exertion (Vedanarayanan and Sinclair, 2013); In silico analysis supports a deleterious effect on protein structure/function
Invitae	RCV001081428	SCV000659759	benign	RYR1-Related Disorders	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003389637	SCV000852232	uncertain significance	RYR1-related condition	2024-01-29	criteria provided, single submitter	clinical testing	The RYR1 c.11061_11063delGGA variant is predicted to result in an in-frame deletion (p.Glu3689del). This variant has been reported in two individuals with no history of malignant hyperthermia, heat illness, or myopathy (Table S3 - Gonsalves et al. 2013. PubMed ID: 24195946). This variant was also reported in an individual with hypertrophied muscles and persistently elevated serum creatine kinase (Vedanarayanan. American Academy of Neurology 2013 Annual Meeting; https://www.aan.com/MSA/Public/Events/Details/2786). This variant is reported in 1.8% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, quality metrics at this site indicate this may not be a reliable estimate of the population frequency. At PreventionGenetics, we have observed this variant in the heterozygous state in ~90 individuals indicating it is likely too common to be a primary cause of an autosomal dominant disorder. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health	RCV000210002	SCV004358192	likely benign	Malignant hyperthermia, susceptibility to, 1	2019-03-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767095	SCV004698542	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	RYR1: BS1, BS2