ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2267G>A (p.Ser756Asn) (rs193922623)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036714 SCV000060369 likely benign not specified 2018-04-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000036714 SCV000235075 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing The S756N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S756N variant was not observed with any significant frequency in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The S756N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. Mutations in nearby residues have not been reported in association with cardiomyopathy, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Ambry Genetics RCV000242970 SCV000319504 likely benign Cardiovascular phenotype 2019-01-25 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV001093912 SCV000356243 likely benign Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-13 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000287643 SCV000356244 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-13 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.
Invitae RCV000379714 SCV000541700 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000036714 SCV000697613 uncertain significance not specified 2017-06-19 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.2267G>A (p.Ser756Asn) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict damaging outcome for this variant. This variant was found in 24/120700 control chromosomes from ExAC at a frequency of 0.0001988, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, this variant has been detected at an allele frequency of ~0.5% (47/10152 chromosomes) in Ashkenazi subpopulation in gnomAD database, further supporting benign outcome. However, five clinical diagnostic laboratories (via ClinVar) have classified this variant as uncertain significance. LMM (via ClinVar) has reported this variant in two Caucasian adults with DCM and one Ashkenazi Jewish adult with HCM and has classified the variant as a VUS, although they do not report if this variant was found with other pathogenic variants in other genes, do not provide any familial co-segregation analysis and have not used ExAC data at that time. Due to the possibility of low penetrance pathogenic variants in the control population and unknown status of cardiological information in control populations, possibility of digenic inheritance in arrythmias and due to lack of functional and clinical data for this variant, the variant has been classified as a VUS-possibly benign until additional evidence becomes available.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000036714 SCV000747970 uncertain significance not specified 2017-06-28 criteria provided, single submitter clinical testing
Color RCV001181067 SCV001346132 likely benign Cardiomyopathy 2018-10-22 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157446 SCV000207190 likely pathogenic Paroxysmal familial ventricular fibrillation 1 2014-03-20 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786207 SCV000924927 uncertain significance not provided 2017-11-01 no assertion criteria provided provider interpretation p.Ser756Asn (c.2267G>A) in the RYR2 gene (NM_001035.2; chr1-237664074-G-A) SCICD Classification: variant of uncertain significance, likely benign based on limited data to associate this gene with disease and relatively high frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: RYR2 has not been associated with HCM Region-level evidence: Per the lab report, this variant is not in one of the regions of RYR2 that is enriched for pathogenic variation. Population data: Highest MAF in Ashkenazi Jewish population: 0.4630%. The variant was reported online in 56 of 138571 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent.

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