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

gnomAD frequency: 0.00001  dbSNP: rs769294223

Total submissions: 6

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	The p.G1275S variant (also known as c.3823G>A), located in coding exon 31 of the RYR2 gene, results from a G to A substitution at nucleotide position 3823. The glycine at codon 1275 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001100939	SCV001257487	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 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 Laboratory Services, Illumina	RCV001100940	SCV001257488	uncertain significance	Arrhythmogenic right ventricular dysplasia 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001100939	SCV004282752	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-09-18	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1275 of the RYR2 protein (p.Gly1275Ser). This variant is present in population databases (rs769294223, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201241).
All of Us Research Program, National Institutes of Health	RCV004804793	SCV005426708	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-03-05	criteria provided, single submitter	clinical testing