ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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)."
Ambry Genetics RCV000618323 SCV000736379 uncertain significance Cardiovascular phenotype 2018-06-04 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001100939 SCV001257487 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 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 Clinical Services Laboratory,Illumina RCV001100940 SCV001257488 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 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.

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