ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14173T>A (p.Tyr4725Asn) (rs876661387)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479972 SCV000565513 likely pathogenic not provided 2015-01-05 criteria provided, single submitter clinical testing A novel Y4725N variant that is likely pathogenic was identified in the RYR2 gene. While the Y4725N variant in the RYR2 gene has not been reported to our knowledge, a variant affecting this same residue, Y4725C, has been reported in association with CPVT but with no segregation data provided (Kawamura M et al., 2013). The Y4725N variant was not observed in approximately 6,000 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The Y4725 variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is highly conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no other missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CPVT (Stenson et al., 2014). Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223747 SCV000280447 uncertain significance not specified 2013-11-13 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Tyr4725Asn (Y4725N; c.14173T>A) in the RYR2 gene (NM_001035.2) Although this specific variant has not been previously reported, a variant at the same amino acid residue, Tyr4725Cys, has been reported in association with CPVT, but with no segregation data provided. It was detected in 1/50 Japanese probands with CPVT (Kawamura et al. 2013). Furthermore, the paralog variant Tyr4796Cys in the related protein RYR1 (the skeletal muscle ryanodine receptor) has been reported in association with central core disease (Monnier et al. 2000). It was a de novo mutation in the proband, and segregated with disease in 5 affected family members. Functional characterization showed that the mutant channel is more leaky of calcium into the muscle cell cytoplasm. This provides strong evidence that altering the corresponding amino acid in RYR1 causes disease. Tyr4725Asn in RYR2 is a conservative amino acid substitution from a polar Tyrosine to a polar Asparagine (with a very different side chain) at a residue that GeneDx reports is highly conserved across species. This Tyrosine is conserved across paralog proteins (RYR1-RYR3: http://cardiodb.org/Paralogue_Annotation/gene.php?name=ryr2). In silico analysis with PolyPhen-2 predicts this variant to be “Probably Damaging” with a score of 0.999. Yano et al. (2006) reported that disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant does fall within the C-terminal disease-causing hotspot. However, no nearby variants (+/-10) are listed in HGMD in association with CPVT (as of 1/28/2015). The variant has not been seen in ~6200 individuals from published controls and publicly available population datasets. Kawamura et al. (2013) did not detect variation at this amino acid in 200 Japanese controls. It is absent from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals not ancestry-matched to our patient. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this codon listed in 1000 Genomes (as of 2/3/2015).

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