ClinVar Miner

Submissions for variant NM_001035.2(RYR2):c.7619A>G (p.His2540Arg) (rs200105499)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252890 SCV000318659 uncertain significance Cardiovascular phenotype 2016-11-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000766722 SCV000235265 uncertain significance not provided 2018-10-05 criteria provided, single submitter clinical testing The H2540R variant has not been published as pathogenic or been reported as benign to our knowledge. Although the H2540R variant is a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nonetheless, this variant has been observed in 50/24018 (0.2%) alleles from individuals of African ethnicity in large population cohorts (Lek et al., 2016). Furthermore, this variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000036792 SCV000918170 benign not specified 2018-10-29 criteria provided, single submitter clinical testing Variant summary: RYR2 c.7619A>G (p.His2540Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 277206 control chromosomes, predominantly at a frequency of 0.0021 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 84 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.7619A>G has been reported in the literature in individuals affected with Cardiomyopathy (Landstrom_2017, Mademon-Soler_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000463061 SCV000554606 likely benign Catecholaminergic polymorphic ventricular tachycardia 2017-05-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036792 SCV000060447 uncertain significance not specified 2013-01-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The His2540Arg variant in RYR2 has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.2% (7/4062) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200105499). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, although the frequency of this variant suggests that it is more likely benign, it is too low to confidently rule out a disease-causing role and additional information is needed to fully assess its clinical significance.

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