Description
iven the lack of case data and weak genotype-phenotype correlation, we also consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The ABCC9 gene is associated with dilated cardiomyopathy and atrial fibrillation. Specific variants have also been associated with Hypertrichotic Osteochondrodysplasia. There is weak case data available for this variant. The variant has been seen in at least 5 unrelated cases of dilated cardiomyopathy (not including this patient's family). We have another patient at our center with this variant who also had early-onset atrial fibrillation (perhaps even as a child) and a cardiac arrest. This other patient also had left ventricular non-compaction (LVNC). This variant has been reported twice in ClinVar, classified as variant of uncertain significance by Blueprint Genetics and the Genome Clinic of Geneva. GeneDx also classifies it as a variant of uncertain significance. A poster by GeneDx indicates that they have seen this variant in 2 patients. Bienengraeber et al. (2004) scanned for mutations in the KATP channel genes of 323 individuals with idiopathic dilated cardiomyopathy. Two heterozygous variants were identified in exon 38 of the ABCC9 gene, one being the c.4570_4572delTTAinsAAAT variant found in our patient. Exon 38 of the ABCC9 gene encodes the C-terminal domain of the protein, which contributes to KATP channel trafficking. Functional studies of these variants found aberrant KATP pore regulation and reduced ATP hydrolytic activities, ultimately reducing the ability of these pores to function properly under stress. The two individuals in this study with ABCC9 variants showed pronounced dilated cardiomyopathy with compromised contractile function (ejection fraction <25%) and ventricular tachycardia. The leucine at codon 1524 is highly conserved across species, as are neighboring amino acids. Other variants (missense and frameshift) have been reported in this codon and a nearby codons (1525); however, none of these have been associated with disease. In total the variant has not been seen in 200 published controls (Hu et al. 2014) and individuals from publicly available population datasets. This variant is not listed in the Genome Aggregation Consortium dataset (http://gnomAD.broadinstitute.org/), which currently includes variant calls on ~140,000 individuals of European, African, Latino, Asian and Ashkenazi Jewish descent (as of 7/2016). However, another frameshift variant at this codon, p.Leu1524Cysfs*4, is present in 139 out of 138,493 individuals in gnomAD (highest MAF is in Europeans at 0.08%). The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Furthermore, according to the Exome Aggregation Consortium Dataset (http://exac.broardinstitute.org/), which includes ~64,000 variant calls on European, African, Latino and Asian descent, the ABCC9 gene appears fairly tolerant to loss of function variation (pLI=0.00).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
