ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.3589C>T (p.Arg1197Cys) (rs778849288)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458091 SCV000551683 uncertain significance Dilated cardiomyopathy 1O 2016-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1197 of the ABCC9 protein (p.Arg1197Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs778849288, ExAC 0.1%). This variant has been reported in the literature in an individual affected with Brugada syndrome and short QT syndrome (PMID: 24439875). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786077 SCV000924709 uncertain significance not provided 2017-01-09 no assertion criteria provided provider interpretation Given the limited evidence to associate ABCC9 with dilated cardiomyopathy, weak case data on this variant and its high minor allele frequency in ethnically-matched controls, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data available for this variant. This variant is absent from ClinVar. The variant has been seen in at least 1 unrelated case of Brugada syndrome and short QT syndrome, but not in any families with dilated cardiomyopathy or atrial fibrillation (not including this patient's family). Hu and colleagues (2014) were the first and only group to associate ABCC9 with Brugada syndrome and/or short QT syndrome: this variant was observed in a 65-year-old male diagnosed with Brugada syndrome and short QT syndrome and it was absent in 200 ethnically-matched (Caucasian) controls. According to the test report, "algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine." Neighboring amino acids are moderately conserved across species. The variant was reported online in 32 of 141,311 individuals (MAF=0.011%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 27 of 9,470 individuals of East Asian descent (MAF=0.14%), 1 of 15,450 individuals of South Asian descent (MAF=0.0032%) and 4 of 63,392 individuals of European (non-Finnish) descent (MAF=0.0032%). Of note, this patient is of East Asian descent. Note that the phenotype of the individuals in these datasets is not publicly available. The datasets are comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. In addition, this variant was absent from a sample of 200 Caucasian controls (Hu et al. 2014).

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