Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Stanford Center for Inherited Cardiovascular Disease, |
RCV000786208 | SCV000924929 | uncertain significance | not provided | 2017-07-21 | no assertion criteria provided | provider interpretation | Our patient had a cardiac arrest at age 19 and was diagnosed with DCM. He has had multiple episodes of syncope and is s/p heart transplant. He had ARVC and DCM genetic testing with the GeneDx laboratory. ARVC testing sequenced 7 genes associated with ARVC: DSC2, DSG2, DSP, JUP, PKP2, RYR2 and TMEM43. A missense variant was identified: p.Tyr3531Cys (Y3531C; c.10592 A>G) in the RYR2 gene. Based on the information reviewed below, we classify it as a variant of unknown significance (VUS). Testing also involved sequencing 38 genes associated with DCM: ACTC1, ACTN2, ANKRD1, CSRP3, DES, EMD, LAMP2, LMNA, MTND1, MTND5, MTND6, MTTD, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, NEXN, PLN, RBM20, SCN5A, SGCD, TAZ, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL, and ZASP. No disease-causing variant was detected in these genes. Deletion/duplication analysis for the following genes associated with DCM and conduction system disease was reported as normal: LMNA, SCN5A, DES. p.Tyr3531Cys (Y3531C; c.10592 A>G) in the RYR2 gene This is a completely novel rare variant. It has not previously been reported in individuals with cardiomyopathies or arrhythmias, nor in apparently healthy controls. p.Tyr3531Cys is a conservative amino acid change, resulting in the replacement of a polar tyrosine with a polar cysteine that is capable of forming disulfide bonds. The tyrosine at this location is absolutely conserved across vertebrate species sequenced, and surrounding amino acids are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging†with a score of 1. GeneDx likewise reports that in silico analysis predicts p.Tyr3531Cys to be damaging to protein structure/function. However, this variant does not fall within any of the mutation “hot spot†regions of the RYR2 gene, and no mutations at nearby codons have been reported in association with ARVC or with an RYR2-related arrhythmia condition (Medeiros-Domingo et al. 2009 & HGMD, via GeneDx; ClinVar as of 7/21/2017). This variant is absent from the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good sequencing coverage at this site. There are no other variants at this codon listed in gnomAD. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient’s ancestry is from Pakistan. |