ClinVar

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variant have been reported to cause dilated cardiomyopathy, 1O (MIM#608569) and ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) (PMID: 31575858). While gain of function variant have been reported to cause Cantu syndrome (MIM#239850). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein sequence affected. (SP) 0219 - This variant is non-coding in an alternative transcript. This variant is non-coding in three out of the four ABCC9 transcripts. Exon expression data indicates that this variant is coding in the skeletal muscle transcript and non-coding in the main cardiac tissue transcript (GTEx Portal). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (145 heterozygotes, 0 homozygotes). (I) 0710 – Other truncating variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Three other truncating variants have conflicting or uncertain interpretations of pathogenicity (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported with conflicting interpretations of pathogenicity in individuals with DCM, atrial fibrillation, Brugada syndrome, arrhythmias, and idiopathic cardiac arrest (PMID: 15034580, 26899768, 31638414, 24439875, 23861362, 28600387, 30847666). This variant has seven VUS entries in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patch clamp functional studies involving site-directed mutagenesis and Xenopus laevis oocytes, indicated that this variant might cause a structural defect of the potassium channel and aberrant ATP-dependent channel gating (PMID: 15034580). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign