ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3380A>G (p.Glu1127Gly) (rs200525962)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171762 SCV000055284 likely benign not provided 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000157454 SCV000207198 uncertain significance Sudden cardiac death 2014-05-14 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769783 SCV000901208 uncertain significance Cardiomyopathy 2016-06-21 criteria provided, single submitter clinical testing
Color RCV000769783 SCV000902956 likely benign Cardiomyopathy 2018-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000036729 SCV000235094 uncertain significance not specified 2015-10-30 criteria provided, single submitter clinical testing This variant is denoted c.3380 A>G p.Glu1127Gly (E1127G) NM_001035.2. The E1127G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. E1127G results in a non-conservative amino acid substitution with a negatively charged Glutamic acid residue with a non-polar Glycine residue at a position that is conserved across species. Another mutation in a nearby residue (A1136V) has been reported in association with CPVT, supporting the functional importance of this region of the protein. This variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the E1127G variant is not located in any of the mutation hot spot" regions in the RYR2 gene (Medeiros-Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CPVT,POSTMORTEM,ARVC,CARDIOMYOPATHY,ARRHYTHMIA panel(s)."
Integrated Genetics/Laboratory Corporation of America RCV000171762 SCV000697621 likely benign not provided 2017-05-30 criteria provided, single submitter clinical testing Variant summary: : The RYR2 c.3380A>G (p.Glu1127Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 136/120770 control chromosomes (including 4 homozygotes) from ExAC at a frequency of 0.0011261, which is approximately 20 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. It is more common in South Asian subpopulation with an allele frequency of 0.0055 (92/16512 chromosomes). This variant has been found in two patients (one with HCM and another with Brugada syndrome) without strong evidence for causality (Bottillo_2015, Le Scouarnec_2015). The HCM patient with this variant also carried another VUS MYBPC3 p.M555T. In ClinVar while three clinical laboratories have classified this variant as likely benign/benign, other three have classified it as VUS; all without evidence for independent evaluation. This variant is also located outside of mutational "hotspots" region (exons 1-16) (Medeiros-Domingo, A et al., 2009; PMID: 19926015). Taken together, this variant is classified as likely benign.
Invitae RCV000477396 SCV000554622 benign Catecholaminergic polymorphic ventricular tachycardia 2018-01-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036729 SCV000060384 likely benign not specified 2015-04-15 criteria provided, single submitter clinical testing p.Glu1127Gly in exon 28 of RYR2: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (92/16512) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs200525962).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845327 SCV000987373 uncertain significance Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000171762 SCV000280450 likely benign not provided 2017-03-20 no assertion criteria provided provider interpretation UPDATE on 3/20/2017: gnomAD shows this variant to have an allele frequency of 0.55% in South Asians, including 5 homozygotes, and to be present in 275 individuals out of the 140,000 in gnomAD total.

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