Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000182666 | SCV000280456 | likely pathogenic | not provided | 2013-05-28 | 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.Gly264Arg (p.G264R, c.790 G>C) in RYR2 We consider the variant likely disease causing, given the variant is segregating with disease in this family, is de novo with seemingly unaffected family members, rare, and that the corresponding variant in RYR1 is implicated in malignant hyperthermia. The variant is novel. The variant is not listed in ClinVar (as of March 17th, 2015). It has been seen in a family with CPVT in our center, with segregation in three first degree relatives. In silico analysis with PolyPhen-2 predicts the variant to be possible damaging. SIFT predicts deleterious. The glycine at codon 264 is conserved across species, as are neighboring amino acids. This is a non-conservative amino acid change (Grantham score 125). I did not find any other variants reported in association with disease at this codon and nearby codons. The GeneDx report notes the variant is in the N-terminal "hot spot", where other variants have been seen in association with CPVT, citing Medeiros-Domingo et al (2009). Unfortunately the authors reported only on the prevalence of variants in various domains in cases, not in controls, so no comparison can be made. In total the variant has not been seen in ~ 6200 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 264 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6200 Caucasian and African American individuals (as of January 9th, 2013). There is also no variation at this codon listed in dbSNP (as of January 2014). There is no variation at codon 264 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of March 17th, 2015). p.Ile2149Val (p.I2149V, c.6445 A>G) in RYR2 GeneDx classifies this variant as a variant of uncertain significance. Given that it is novel we too classify it as a variant of uncertain significance. The variant is novel (as of March 17 2015). The proband's mother tested negative for the variant so it most likely was inherited from the proband's father, who has not been evaluated (though it could also be de novo in the proband). In silico analysis predicts the variant to be possibly damaging. The isoleucine at codon 2149 is conserved across species, as are neighboring amino acids. This is a conservative amino acid change with a Grantham score of 29. I found one other variant reported in association with disease at a nearby codon (p.Gly2145Arg). The corresponding variant in the paralogue RYR1 has been implicated in malignant hyperthermia (p.Gly248Arg). In total the variant has not been seen in ~6200 individuals from publicly available population datasets. There is no variation at codon 2149 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6200 Caucasian and African American individuals (as of January 2014). There is also no variation at this codon listed in dbSNP (as of January 2014). There is no variation at codon 2149 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of March 17th, 2015). |