ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.3461G>A (p.Arg1154Gln) (rs387907209)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256056 SCV000322065 pathogenic not provided 2016-01-08 criteria provided, single submitter clinical testing The R1154Q pathogenic variant in the ABCC9 gene has been reported previously in several unrelated individuals with an ABCC9-related disorder (Harakalova et al., 2012; van Bon et al., 2012; Czeschik et al., 2013). The R1154Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies showed the R1154Q variant reduced sensitivity of the potassium channel to ATP-dependent inhibition (Harakalova et al., 2012). The R1154Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. We interpret R1154Q as a pathogenic variant.
Invitae RCV000559460 SCV000639234 pathogenic Dilated cardiomyopathy 1O 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1154 of the ABCC9 protein (p.Arg1154Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs387907209, ExAC no frequency). This variant has been shown to arise de novo in several individuals affected with Cantu syndrome (PMID: 22608503, 23307537). ClinVar contains an entry for this variant (Variation ID: 31947). Experimental studies have shown that this missense change reduces ATP-mediated potassium channel inhibition (PMID: 22610116). A different missense substitution at this codon (p.Arg1154Trp) has been determined to be pathogenic (PMID: 22608503, 26871653). This suggests that the arginine residue is critical for ABCC9 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000024625 SCV000050491 pathogenic Hypertrichotic osteochondrodysplasia 2012-06-08 no assertion criteria provided literature only

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