ClinVar Miner

Submissions for variant NM_001035.2(RYR2):c.10231-4T>C (rs117180147)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253861 SCV000318539 benign Cardiovascular phenotype 2016-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Other strong data supporting benign classification,General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768786 SCV000900156 benign Cardiomyopathy 2016-08-25 criteria provided, single submitter clinical testing
Color RCV000768786 SCV000910920 benign Cardiomyopathy 2018-03-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587853 SCV000203486 uncertain significance not provided 2013-11-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000229365 SCV000356407 likely benign Catecholaminergic polymorphic ventricular tachycardia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000333639 SCV000356408 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587853 SCV000697599 benign not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.10231-4T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 67/58520 control chromosomes (2 homozygotes) at a frequency of 0.0011449, which is approximately 21 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Invitae RCV000229365 SCV000285683 benign Catecholaminergic polymorphic ventricular tachycardia 2017-12-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154633 SCV000204307 benign not specified 2015-06-26 criteria provided, single submitter clinical testing c.10231-4T>C in intron 70 of RYR2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 1.3% (61/4770) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs117180147).
PreventionGenetics RCV000154633 SCV000306016 likely benign not specified criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000154633 SCV000280439 uncertain significance not specified 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. Genetic testing: The patient had genetic testing via the Pan Cardio panel with the Ambry laboratory. The test included sequencing of 79 genes associated with hereditary arrhythmias and cardiomyopathies: ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALR3, CASQ2, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, EYA4, FXN, GATA4, GLA, GPD1L, ILK, JAG1, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ8, KCNQ1, LAMP2, LDB3/ZASP, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2.5, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SGCD, SNTA1, TAZ, TBX1, TBX5, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL. Results reported on April 10th, 2013 show that no disease-causing variants in genes associated with either long QT or hypertrophic cardiomyopathy were found. Testing did identify several variants of uncertain significance: - ANK2 p.Arg996Gln (c.2987G>A, p.R996Q). Ambry classifies this as a variant of uncertain significance. Based on the data reviewed below we consider it a variant of uncertain significance. - ANK2 p.Leu3143Val (c.9427C>G, p.L3143V). Ambry classifies this as a variant of uncertain significance. Based on the data reviewed below we consider it a variant of uncertain significance. -RYR2 c.10231-4T>C. Ambry classifies this as a variant of uncertain significance, suspected benign. Based on the data reviewed below we consider it a variant of uncertain significance, probably benign. The available data on each of these is reviewed below. Given the large number of genes included on this panel and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have. Testing also identified several missense variants in TTN: - TTN c.20722G>A p.V6908I. Ambry classifies this as a variant of uncertain significance. - TTN c.53083A>G p.T17695A. Ambry classifies this as a variant of uncertain significance. - TTN c.71996A>G p.N23999S. Ambry classifies this as a variant, suspected benign. It is unclear at this time what role, if any, TTN missense variants play in causing inherited cardiovascular disease. In general population samples there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone with this panel would uncover such a variant. As such we would generally consider all TTN missense variants to be variants of uncertain significance. ANK2 p.Arg996Gln (c.2987G>A, p.R996Q) Ambry classifies this as a variant of uncertain significance. Based on the data reviewed below we consider it a variant of uncertain significance. The variant has not been reported in association with disease but it has been seen in one individual from a general population sample. It is unknown at this time whether this variant and the other ANK2 variant are on the same chromosome or opposite chromosomes. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and SIFT predicts it to be deleterious (per the Ambry report). The arginine at codon 996 is completely conserved across species, as are neighboring amino acids. In total the variant has been seen in 1 of ~7592 individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (per Ambry report, as of April 26th, 2013). Note that this dataset does not match the patient's ancestry (Asian). It was observed in 1 of 1092 individuals in 1000 genomes (per Ambry report). The variant is listed in dbSNP (rs200124480), which points to the 1000 genomes data. The ANK2 gene encodes ankyrin-2 (aka ankyrin-B), which links integral membrane proteins to the underlying spectrin-actin cytoskeleton and plays a role in signaling and membrane protein trafficking and regulation. Mohler et al (2003) first proposed a link between ANK2 and long QT syndrome. A missense variant in ANK2 co-segregated with disease in 24 affected members of a large French kindred. They had a mixed phenotype of long QT syndrome, sinus node dysfunction and atrial fibrillation, which has been labeled long QT type 4. Inheritance was autosomal dominant. Sinus node dysfunction was detectable in utero while atrial fibrillation was only observed in adulthood. Mice heterozygous for a null variant in ANK2 were shown to be haploinsufficient for ankyrin-2 and to have arrhythmias similar to those seen in the human patients. In vitro studies revealed disruption of the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1, 4, 5- triphosphate receptors. Altered calcium signaling was also observed and was considered the rationale for arrhythmia. Additional cases of long QT and other arrhythmic phenotypes associated with ANK2 have since been reported (see Smith et al 2012 for review). RYR2 c.10231-4T>C The variant has not been reported in association with disease but it has been seen in general population samples. This variant is 4 nucleotides before exon 71 and could potentially affect splicing. However, Ambry notes in the report that they used the BDGP and ESEfinder splice site prediction tools and both predicted no significant effect on the native acceptor splice site. In total the variant has 8 of ~5813 individuals from publicly available population datasets. Of note, it appears to be fairly common in individuals of Asian ancestry (which matches the patient's ancestry). The variant was recently reported online in 2 of 1456 African-American individuals in the NHLBI Exome Sequencing Project dataset, but not in ~3263 Caucasian individuals in that dataset (as of April 26th, 2013, per Ambry report). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Note also that this dataset does not match the patient's ancestry (Asian). The variant is also listed in dbSNP (rs117180147), which points to the 1000 genomes data (as of April 26th, 2013). Per the dbSNP entry, it was seen in 4/120 Japanese chromosomes (presumably 4/60 individuals). The Ambry report notes that within the 1000 genomes data the variant was seen in 3/194 Han Chinese chromosomes (presumably 3/92 individuals). Ambry also notes that the variant was seen in 6 of 2188 chromosomes in 1000 genomes (presumably 6 of 1094 individuals). RYR2 variants have been associated with catecholaminergic polymorphic ventricular tachycardia and in a few cases a form of cardiomyopathy that somewhat resembles arrhythmogenic right ventricular cardiomyopathy. They have not to date been associated with either long QT syndrome or hypertrophic cardiomyopathy.

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