ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.4570_4572delinsAAAT (p.Leu1524fs) (rs869025349)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208420 SCV000263750 uncertain significance Primary dilated cardiomyopathy 2015-11-05 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000449617 SCV000537749 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-07-05 criteria provided, single submitter clinical testing
Invitae RCV000470248 SCV000551682 uncertain significance Dilated cardiomyopathy 1O 2020-01-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1524Lysfs*5) in the ABCC9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the ABCC9 protein. This variant is reported as two separate changes in population databases (c.4569_4570insAAA, ExAC 0.1% and c.4571_4572delTA, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with dilated cardiomyopathy, Brugada syndrome and idiopathic cardiac arrest (PMID: 15034580, 24439875, 26899768, 28600387). ClinVar contains an entry for this variant (Variation ID: 222477). This variant has been reported to affect ABCC9 protein function (PMID: 15034580). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ABCC9 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000601900 SCV000711368 uncertain significance not specified 2018-05-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Leu1524fs var iant in ABCC9 has been reported in 2 individuals with DCM (Bienengraeber 2004, C uenca 2016) and 1 individual with Brugada Syndrome (Hu 2014), but has also been identified in 0.08% (107/126560) of European chromosomes by the Genome Aggregati on Database (gnomAD,; dbSNP rs139703258 and rs7 61784169). In vitro functional studies provide some evidence that the p.Leu1524f s variant may impact protein function (Bienengraeber et al. 2004); however, thes e types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein?s amino acid seque nce beginning at position 1524 and leads to a premature termination codon 5 amin o acids downstream. This termination codon occurs within the last exon of the ge ne and is likely to escape nonsense mediated decay, resulting in a truncated pro tein. In summary, while the clinical significance of the p.Leu1524fs variant is uncertain, the frequency data suggests that it is more likely to be benign. ACMG /AMP Criteria applied. BS1, PS3_Supporting.
Ambry Genetics RCV000617732 SCV000735680 uncertain significance Cardiovascular phenotype 2018-02-07 criteria provided, single submitter clinical testing Insufficient evidence
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786079 SCV000924711 uncertain significance not provided 2017-04-06 no assertion criteria provided provider interpretation 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 (, 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 (, 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).

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