ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3596A>G (p.Asp1199Gly) (rs149760466)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036733 SCV000060388 uncertain significance not specified 2013-09-20 criteria provided, single submitter clinical testing The Asp1199Gly variant in RYR2 has not been previously reported in any other ind ividuals with cardiomyopathy, but has been identified in 1/196 Italian chromosom es by the 1000 Genomes Project (dbSNP rs149760466). Computational analyses (bio chemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. This varian t is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicing, though this i nformation is not predictive enough to rule out pathogenicity. In summary, addit ional information is needed to fully assess the clinical significance of this va riant.
Integrated Genetics/Laboratory Corporation of America RCV000036733 SCV000918162 uncertain significance not specified 2018-04-09 criteria provided, single submitter clinical testing Variant summary: RYR2 c.3596A>G (p.Asp1199Gly) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Although the variant is the third nucleotide of an exon-intron junction, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 244970 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3596A>G has been reported in the literature in individuals affected with Cardiomyopathy (Pugh_2014, Walsh_2016). However, these reports do not provide unequivocal conclusions about an association of the variant with Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported (TTN c.79117+2T>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

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