ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3823G>A (p.Gly1275Ser) (rs769294223)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618323 SCV000736379 uncertain significance Cardiovascular phenotype 2016-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000182716 SCV000235098 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing p.Gly1275Ser (GGC>AGC): c.3823 G>A in exon 31 of the RYR2 gene (NM_001035.2). The G1275S variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The G1275S variant was not observed in approximately 6000 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 G1275S variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The G1275 residue is conserved across species. In silico algorithms are not consistent in their predictions but at least two concur that G1275S is possibly damaging to the protein structure/function. However, the G1275S variant is not located in any of the mutation hot spot" regions in the RYR2 gene (Medeiros-Domingo A et al., 2009), and no mutations in nearby residues have been reported in association with cardiomyopathy, indicating thisregion of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if G1275S is a disease-causing mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s)."

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